mitochondria - exam Flashcards
Origin of Mitochondria
endosymbiotic theory
chatgpt
Mitochondria evolved from a bacterial ancestor via endosymbiosis and have retained some features of their prokaryotic origin, such as a circular genome and independent replication.
Structure/Organisation
outer membrane
chatgpt
Permeable to small molecules; contains channels like VDAC, TOM.
Structure/Organisation
Inner membrane
chatgpt
Site of OXPHOS; contains ETC complexes, ATP synthase, cardiolipin.
Structure/Organisation
Cristae
chatgpt
Increase surface area for energy production.
Structure/Organisation
Matrix
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Contains mtDNA, ribosomes, enzymes for TCA cycle.
Structure/Organisation
Nucleoid
chatgpt
mtDNA-protein complexes organized by TFAM for replication and inheritance.
Function of Mitochondria
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ATP production via the TCA cycle and oxidative phosphorylation
Apoptosis regulation via cytochrome c release
Calcium buffering
Lipid metabolism (e.g. β-oxidation, cardiolipin synthesis)
Reactive oxygen species (ROS) generation and detoxification
Innate immune signaling (e.g. via mtDNA or metabolic intermediates)
Metabolic signaling (e.g. acetyl-CoA in epigenetic regulation)
Mitochondrial Dynamics
Biogenesis
chatgpt
Regulated by transcription factors like PGC-1α and TFAM.
Mitochondrial Dynamics
Fission & Fusion:
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Control mitochondrial size, number, and quality (Drp1, Mfn1/2, OPA1).
Mitochondrial Dynamics
Mitophagy
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Removes damaged mitochondria for quality control.
Mitochondrial Dynamics
Trafficking
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Ensures correct spatial distribution (via microtubules and actin).
Mitochondrial Dynamics
Developmental & stress adaptation:
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Dynamic shape and positioning allow mitochondria to meet changing cellular demands.
ORIGIN
endosymbiosis theory
Mitochondria were originally bacterial-like cells that are capable of generating energy through oxygen consumption.
About 2 billion years ago, these cells were engulfed by a host cell with a nuclear like structure (Probably occurred multiple times during evolution)
when it happened at the time the oxygen level started to increase in the earth’s atmosphere, a mutually beneficial relationship began to form.
- The host cell provided protection and nutrients, and the engulfed bacterium provided extra cellular energy in the form of ATP.
Over time, this symbiotic relationship eventually became permanent.
Today, if you look at a typical animal mitochondrion, it can contain up to 2000 different proteins, but only 13 of them are encoded by the mitochondrial DNA.
- Therefore, >99% of mitochondrial proteins are encoded by the nuclear DNA. They are translated in the cytoplasm and imported into mitochondria to carry out all sorts of functions.
STRUCTURE/ORGANISATION
what is mtDNA important for
important for energy production.
STRUCTURE/ORGANISATION
variation
mitochondria in different regions of the cell have different sizes and shapes. The mitochondrial morphology can also varies a lot depending on the cell type and cell status, and environmental factors such as the level of O2 and glucose
different tissues
STRUCTURE/ORGANISATION
double membrane
Outer membrane around entire structure
- Underneath is the inner membrane, which folds inwards extensively to form a structure called cristae.
o These cristae provide the membrane area for OXPHOS, as all the respiratory complexes are located here.
STRUCTURE/ORGANISATION
where is the mtDNA
The mitochondrial DNA (mtDNA), are in the matrix along with many other metabolites and enzymes involved in the Krebs cycle for energy production.
STRUCTURE/ORGANISATION
lipids in membranes
The outer and inner membranes are phospholipid bi-layers made of various lipid species.
STRUCTURE/ORGANISATION
lipids in membranes
outer mitochondrial membrane
- phosphatidylcholine (PC)
- phosphatidylethanolamine (PE)
- also contains cholesterol.
o is similar to the endoplasmic reticulum
o These lipids are essential for maintaining the membrane’s flexibility and facilitating the exchange of molecules between the cytoplasm and the intermembrane space.
STRUCTURE/ORGANISATION
lipids in membranes
inner mitochondrial membrane
- rich in PC and PE,
- Cardiolipin (phospholipid) –> found only in mitochondria
o Important for membrane curvature
o possesses a glycerol head group and 4 fatty acyl chains, and together they form a cone-shaped structure.
o cone shape facilitates the membrane bending to form cristae, as it allows the membrane to form sharp curves.
STRUCTURE/ORGANISATION
lipids in membranes
synthesizing
Mitochondria can synthesize PE and CL, while other phospholipids need to be obtained from other organelles.
STRUCTURE/ORGANISATION
Protein complexes embedded in membranes:
outer membrane contains
- many channel forming proteins
o controls what goes into and out of mitochondria.
o eight channel‐forming proteins or protein complexes found in the outer membrane of yeast mitochondria.
Tom40, Sam50, Mdm10, and Mim1 are involved in protein import
VDAC is the main channel for small metabolites and ions.
The transported substrates for the other three channels remain less well-defined. Tom40, Sam50, and VDAC are highly conserved and found in the outer membrane of plant and animal mitochondria.
STRUCTURE/ORGANISATION
Protein complexes embedded in membranes:
The outer membrane translocase works together with…
with translocase complexes on the inner membrane to import proteins into the mitochondrial matrix.
- most mitochondrial proteins are encoded by the nuclear genomes (made in the cytoplasm, need to be imported into mitochondria)
- These proteins bear signals that allow them to be recognised by the outer and inner membrance translocase complexes, which will pull them into the mitochondria.
STRUCTURE/ORGANISATION
Protein complexes embedded in membranes:
the inner membrane
- the respiratory complexes required for oxidative phosphorylation.
o Therefore, the amount of cristae reflects the OXPHOS capacity of a given mitochondrion. - Junction between inner membrane and cristae membrane also contains large complexes called MICOS.
o The MICOS facilitates membrane bending and allows formation of cristae junction.
MITOCHONDRIAL DNA
mtDNA in different species:
Small differences to the genetic code and subtle differences between species.
MITOCHONDRIAL DNA
mtDNA in different species:
ANIMALS
size: 13-42kb
non-coding: very low
mutation rate: high or varies
non-canonical genetic code: yes (e.g. invertebrate/vertebrate)
structure: mostly single circular but can be multiple circular or linear with telomere
MITOCHONDRIAL DNA
mtDNA in different species:
FUNGI
size: 11-80kb
noncoding: variable
introns: yes
mutation rate: low
non-canonical genetic code: yes (yeast/several others)
structure: mostly single circular but can be multiple circular or linear with telomere
MITOCHONDRIAL DNA
mtDNA in different species:
PLANTS
size: 184-11,400 kb
noncoding: very high
introns: yes
mutation rate: very low
non-canonical genetic code: no (universal genetic code)
structure: mostly single circular but can be multiple circular or linear with telomere
MITOCHONDRIAL DNA
mtDNA in different species:
fungal and plants mtDNA
Fungal and plants mtDNA are much bigger in size.
- contain many non-coding sequences
- repetitive sequences of unknown origin or transposon like elements.
fungal mtDNA does not use canonical genetic code, whereas plant genomes do.
MITOCHONDRIAL DNA
a typical animal mitochondria genome
The human mtDNA is about 16.5 kb
- It encodes 13 proteins, 22 tRNAs and 2rRNAs.
- has a single non-coding region,
o also known as control region or D-loop region.
o This region contains replication origin, transcription promoters and some repetitive sequences with unknown function
MITOCHONDRIAL DNA
insect mtDNA comparrison
The insect mtDNA has the same coding capacity but the non-coding region could be longer, as shown here for D. melanogaster.
- The gene order is also different from the mammalian version. These 13 proteins, together with the proteins encoded by the nuclear genome, form respiratory chain complexes.
MITOCHONDRIAL DNA
The nuclear and mitochondrial genomes have to be…
compatible in order to assemble functional complexes for OPXHOS.
MITOCHONDRIAL DNA
linear structures
In some species, mtDNA are organised as multiple linear structures.
For example, in one species of Amoebidium, which is a unicellular symbiotic eukaryote, its 300 kb mtDNA is consist of several hundreds of linear molecules. These linear fragments share a short common terminal repeat.
MITOCHONDRIAL DNA
eukaryotes
Some eukaryotes contain mitochondrial like structure, but has lost mtDNA entirely.
MITOCHONDRIAL DNA
mitocondrial nucleoids
– DNA + protein structure
* A cell can hundreds of mitochondria, and each mitochondria can have multiple copies of mtDNA as shown in these microscopic images.
o These mtDNA are organized in a DNA-protein complex called nucleoid.
o main protein of the nucleoid is called TFAM
o TFAM to mtDNA is like histone to the nuclear DNA
o It bends mtDNA and pacts it into small puncta looking like these dots in the super-resolution image shown.
MITOCHONDRIAL DNA
mitocondrial nucleoids
what does it provide
- Nucleoid packaging provides an efficient means to ensure that the genome is distributed throughout the mitochondrial network.
o A nucleoid is about 31-318 nm in size and can contain multiple copies of mtDNA.
MITOCHONDRIAL DNA
inheritance
Maternal inheritance
- Not only the organisation of mtDNA is different from the nuclear DNA, its transmission pattern is also different.
- For almost all eukaryotes, mtDNA follows strict uniparental inheritance. Most animals, including us humans, get their mtDNA from our mothers.
MITOCHONDRIAL DNA
Insights from examining mtDNA:
- A study published in 1987 proposed that mtDNA in modern humans was inherited from one common female in Africa about 200,000 years ago known as the mitochondrial eve.
o This confirms the recent African Origin hypothesis of modern humans, which was initially put forward based on fossil evidence.
MITOCHONDRIAL DNA
Insights from examining mtDNA:
better understanding of migrations that shaped human population
o There are 27 major mitochondrial haplotypes within the human population.
o The L lineages are considered to be the most ancient and African.
o Around 70,000 years ago, one of the L lineages L3 migrated out the Africa and gave rise to three macrohaplogroups M, N and R, which cover all variations observed outside Africa.
o Each haplogroup contains many different subgroups that carry various sequence polymorphisms. For example, the European mtDNA haplogroup N can be further divided into these sub-types.
MITOCHONDRIAL DNA
Mechanisms ensuring maternal mtDNA inheritance
- Initially, people think that this is simply because of a dilution effect: eggs usually contains way more mitochondria than sperm, so the maternal genotype is overly represented in the offspring.
o But this model still allows some paternal genomes to be transmitted, which we know is extremely rare. This model also does not explain uniparental inheritance in species where the male and female gametes are similar in size.
MITOCHONDRIAL DNA
Mechanisms ensuring maternal mtDNA inheritance
recent evidence
- Recently, evidence showing that there are active mechanisms to specifically eliminate paternal mitochondria before and after fertilization started to emerge.
o For example, studies in humans, mice, Japanese rice fish, Drosophila and C.elegans, revealed that the transmitted paternal mitochondria are recognised and degraded soon after fertilisation by autophagy-like pathways.
o However, for most of these species, the paternal mtDNA is eliminated even before fertilisation.
MITOCHONDRIAL DNA
Multiple mechanisms to prevent paternal leakage
in drosophila
In drosophila parental mtDNA is eliminated in late spermatogenesis and PLOG is required
Paternal mitochondria are further eliminated in the egg upon fertilisation through some ubiquitin and autophagic pathways
MITOCHONDRIAL DNA
Multiple mechanisms to prevent paternal leakage
in humans
- A mature human sperm contains about 50-70 mitochondria, but together, they carry less than 1 copy of mtDNA.
o So most of the paternal maternal genomes are eliminated during late stage of spermatogenesis. - This is followed by the elimination of paternal mitochondria in zygotes after fertilization.
o The paternal mitochondria are marked before entering the eggs.
o These marks allow machinery in eggs to degrade only the paternal mitochondria, not those from the maternal side.
MITOCHONDRIAL DNA
Multiple mechanisms to prevent paternal leakage
in fish
- most of the mtDNA are eliminated during sperm matureation.
- After the fertilization, the leftover mtDNA inside the sperm mitochondria will then be degraded first, which is followed by the degradation of paternal mitochondria.
MITOCHONDRIAL DNA
Multiple mechanisms to prevent paternal leakage
in C. elegans
- the elimination depends mainly on autophagy after fertilization
MITOCHONDRIAL DNA
Multiple mechanisms to prevent paternal leakage
however…..
Nevertheless, despite these mechanisms, paternal leakage has been reported in various species, including humans.
- One paper published in PNAS recently made the headline, which showed biparental inheritance of mtDNA in three unrelated Chinese families.
- But this study has remained debatable, as some concerns of sample contaminations were raised later by other scientists in the field, so it is not clear whether these are real paternal leakage cases or experimental artefacts.
o Data not reliable
o Contamination, error
o Debatable
MITOCHONDRIAL DNA
Multiple mechanisms to prevent paternal leakage
exception
The uniparental inheritance is highly conserved in eukaryotes.
But there are some exceptions.
One of the well characterized alternative transmission patterns is known as doubly uniparental inheritance.
MITOCHONDRIAL DNA
Multiple mechanisms to prevent paternal leakage
exception: doubly uniparental inheritance.
- This has been reported in over 100 species from different bivalve orders, such as blue mussels.
- These species are characterized by the presence of two distinct gender-associated mitochondrial genotypes: one transmitted through eggs (F) and one transmitted through sperm (M).
- Both genotypes enter the zygote, but if you look at the female progeny, you can only find the F genotype, and if you look at the male progeny, they contain the F type in their somatic tissues, but in the germline, they only have the M-type.
- So basically, F-type is transmitted only through eggs and M-type is only transmitted from fathers to sons, so both genomes are transmitted uniparentally. That is why it is called doubly uniparental inheritance.
MITOCHONDRIAL DNA
HOMOPLASMY VS HETEROPLASMY
- Most of us are heteroplasmic with low levels of mtDNA mutations in various tissues
some mt genomes replicate more than other
shifts relevant abundance of WT and mutated genomes
MITOCHONDRIAL DNA
HOMOPLASMY VS HETEROPLASMY
Heteroplasmy:
a constant changing mtDNA population
- Heteroplasmy represents a constantly changing mtDNA population. When a mutation first arises, it is often present in low levels. Most of the time, it will stay low or be eliminated.
- But sometimes it can increase its abundance during development and aging to cause defects.
o E.g. can be born with defect -> wont necessarily develop symptoms
o But can develop due to constant turnover the mitochondria and relaxed replication of mtDNA
MITOCHONDRIAL DNA
HOMOPLASMY VS HETEROPLASMY
mtDNA linked disorders
- > 700 pathogenic mutations associated with >50 types of mitochondrial diseases
- Affect 1 in 4300 people
- Most mutations are heteroplasmic
- Some mutations have been linked to other conditions
o E.g. cancer, diabetes, neurodegenerative disorders and ageing
MITOCHONDRIAL DNA
HOMOPLASMY VS HETEROPLASMY
mtDNA genetic disorders
- Mitochondrial diseases can also be causes by mutation in the nuclear DNA
MITOCHONDRIAL DNA
Limited tools to edit animal mtDNA
- No established methods to deliver DNA and RNA into mitochondria
- Mitochondrial-targeted nucleases can selectively get rid of detrimental mtDNA copies but require extensive optimization in cloning and delivery
MITOCHONDRIAL DNA
Limited tools to edit animal mtDNA
three parent babies
mitochondrial replacement therapy
- 1st 3 parent baby boy born in 2016 (Mexico), 1st girl in 2017 (ukraine)
- an egg from a healthy donor with functional mtDNA is obtained, and the nucleus of this egg is removed.
- This is followed the transfer of the nucleus from the egg that carries mitochondrial mutations.
- These procedures result in an egg with the nuclear DNA from the original mother, and mitochondrial DNA from a second mother.
FUNCTION
powerhouse of the cell
- primary function is to generate ATP.
FUNCTION
energy production
- TCA Cycle or Kreb Cycle
- series of biochemical reactions that release the energy stored in the chemical bonds of glucose to generate electron donors such as NADH. - the electron donors are fed into the respiratory complexes to create a flow of protons across the membrane.
- There are five respiratory complexes: I, II, III, IV and IV.
- This proton gradient is then used by the complex IV, also known as the ATP synthase complex to convert ADP into ATP.
- This delivery of electrons and gradient-driven synthesis of the ATP part is known as oxidative phosphorylation.
FUNCTION
energy production
ATP molecules
The whole process can generate 36 ATP molecules from one molecule of glucose. This is much more efficient than glycolysis, which occurs in the cytoplasm and only generates 2 molecules of ATP.
FUNCTION
other central roles
- programmed cell death
- lipid metabolism
- calcium signalling
- innate immune response
- cell differentiation and etc.
FUNCTION
recently have been linked to…
Recently, mitochondrial function and mitochondrial DNA have also been linked to aging and various age-related conditions.
DYNAMICS
Mitochondria are dynamic organelles that can easily change their amount, morphology and subcellular distributions. These activities allow them to meet the energy demands associated with growth, development, metabolic changes.
DYNAMICS
Mitochondria turnover frequency: biogenesis and degradation
When a cell divides, more mitochondria need to be made.
- even in non-dividing cells, mitochondrial biogenesis will occur regularly.
- to replace the dysfunctional old mitochondria.
- Different tissues renew their mitochondria at different rates.
o For instance, the average lifespan of mitochondria in the human brain is thought to be around 30 to 40 days.
DYNAMICS
Mitochondria turnover frequency:
When more mitochondria are needed
cells can generate new ones to increase the overall amount.
DYNAMICS
Mitochondria turnover frequency:
key players:
- PGC-1α acts as a master regulator. Responding to energy stress and nutrient availability, it interacts with
- NRF1 and some other coactivators to stimulate the transcription of nuclear-encoded mitochondrial proteins.
- TFAM is the other transcription factor. It upregulates mtDNA transcription and replication.
DYNAMICS
Mitochondria turnover frequency:
This synchronised upregulation of nuclear and mitochondrial encoded factors ensures…
the proper assembly and function of new mitochondria.
DYNAMICS
Mitochondria turnover frequency:
PARK2 and PINK1
PARK2: ubiquitin ligase -> links to neurodegenerative diseases
PINK1: collects on surface of mitochondria when mitochondria is damaged (recruits PARK2)
DYNAMICS
Mitophagy:
- a process that removes damaged mitochondria from a cell, helping to maintain mitochondrial health
DYNAMICS
mitochondria trafficking:
- important aspect of mitochondrial dynamics. This movement allows precise positioning and distribution of mitochondria within cell to accommodate local needs.
DYNAMICS
mitochondria trafficking: Microtubule based
crucial in
- crucial in cells with elongated shaped, such as neurons, where mitochondria need to be transported over long distances to provide energy at synapses.
DYNAMICS
mitochondria trafficking: Microtubule based
long distance movement
- long-distance movement is mainly mediated by microtubules through molecular motors kinesin and dynein.
DYNAMICS
mitochondria trafficking: Microtubule based
motor proteins
- Mitochondria are not directly attached to these motor proteins.
o require motor adaptor proteins such as miro and milton, which link the mitochondria to kinesin and dynein and allow mitochondria to be transported towards plus or minus end of the microtubule.
DYNAMICS
mitochondria trafficking: actin based
- Recently, actin has also been found to regulate mitochondrial movement in cells, mainly controlling short-range motility, and local anchoring.
DYNAMICS
mitochondria trafficking: actin based
how does it work
- actin forms a cable around mitochondria, limiting their movement to a specific area.
o This mechanism helps mitochondria move along with the actin network during cell division to ensure an even segregation of mitochondria into the newly formed daughter cells.
o It can also prevent mitochondria from moving long distances via the microtubules.
DYNAMICS
mitochondria trafficking: actin based
what motor proteins
- So far, several myosin motor proteins have been identified to facilitate actin-based mitochondrial motility/anchoring.
o For example, myo19 can localise to mitochondria’s outer membrane, and drive mitochondria movement toward the plus end of the actin filament.
o This will target mitochondria to stress-induced filopodia and coordinate mitochondrial inheritance during cytokinesis.
o Myosin 5 and 6 have been found to anchor mitochondria to actin filaments in axons and stop microtubule-based movement.
DYNAMICS
mitochondria trafficking: actin based
population that dont seem to move?
- There is a population of mitochondria that donot seem to move.
o These mitochondria are anchored to the local actin filament by these two myosins to prevent microtube based movement.
DYNAMICS
fission and fusion
Mitochondria undergo frequent fission and fusion
- the mitochondrial morphology also constantly changes due to frequent fusion and fission events.
- two small mitochondria in this region move towards each other and fuse to form a larger one.
- These fusion and fission events allow mitochondria in the cell to exchange content and genetic materials.
DYNAMICS
fission and fusion:
key players
- Since mitochondria have double membranes, the fusion process involves outer membrane fusion followed by inner membrane fusion, happening closely in time.
o Two proteins: Mfn1 and Mfn2 are required for outer membrane fusion. (needs to be presented on both sides)
o Opa1 mediates inner membrane fusion. (only needs to be presented on one side)
DYNAMICS
fission and fusion:
key players: central mediator
- The central mediator of mitochondrial fission Drp1.
o This protein is recruited from a cytoplasm onto the mitochondrial surface with the helper of these receptors.
o Once on mitochondria, Drp1 self-assembles into spiral structures that wrap around and constrict mitochondrial tubules to allow fission.
DYNAMICS
fission and fusion:
key players: ER
- ER also plays a role in mitochondria fission by wrapping around mitochondria at the site of Drp1 to further facilitate the separation of the two mitochondria.
DYNAMICS
fission and fusion:
balance
The balance between fusion and fission determines mitochondrial size, number, and shape.
DYNAMICS
fission and fusion:
balance - physiological consequences
o the morphology of mitochondria can directly impact their bioenergetic function, with elongated mitochondria sometimes linked to more efficient ATP production.
DYNAMICS
fission and fusion:
balance - excessive fission
Excessive fission can lead to the release of pro-apoptotic factors such as cytochrome c, triggering cell death, while fusion can delay apoptosis, acting as a protective mechanism.
DYNAMICS
fission and fusion:
shape
In certain cells, shape has functional consequences, like in neurons where the transport of small mitochondria to terminals may be more efficient.
DYNAMICS
fission and fusion:
what does fusion allow
Fusion allows functional mitochondria to complement each other by sharing components, diluting the effects of mtDNA mutations or localized damage.
DYNAMICS
fission and fusion:
what does fission allow
Fission allows damaged parts to break off and get degraded by mitophagy without affecting the rest of the organelle.
DYNAMICS
fission and fusion:
during cell cycle
- Allows more mitochondria to be produced
- Allows population to be evenly segregated into two daughter cells
DYNAMICS
during development:
dramatic mitochondrial dynamics that occur during spermatogensis.
DYNAMICS
during development:
example
Drosophila melanogaster.
In this image, mitochondria, labeled in green, exhibit distinct patterns for sperm cells at different developmental stages.
In some sperm cells, they are evenly distributed, while in others, they form a single large cluster.
Additionally, certain cells show mitochondria arranged in long, stripe-like structures, demonstrating the remarkable adaptability of mitochondrial organization during development.
- Mitochondria changes during spermatogenesis in fly
- As develops forms ball next to nucleus
- Final stage can see long tubes of mitochondria
DYNAMICS
during development:
Mitochondria transformation in human and mouse sperm
mammals, mitochondria in mature sperm do not fuse to form nebenkern, but they also undergo drastic morphological changes to form a structure called mitochondrial sheath. This sheath wraps around the axoneme in the middle piece of the sperm flagellum.
DYNAMICS
during development:
Mitochondria transformation in human and mouse sperm
various models
Various models have been proposed to explain how mitochondrial sheath is formed. According to this paper, there are at least four stages. It starts with the alignment of mitochondria, followed by a change in mitochondrial shape, becoming more elongated, eventually taking on a rod shape, and wrapping around each other.
DYNAMICS
Clinical syndromes linked to imbalanced mitochondrial dynamics
alzheimers
parkinsons
nonalcoholic fatty liver
cardiac ischemia reperfusion injury
CROSS TALK WITH OTHER ORGANELLES
- To act as a signalling hub through:
o Direct contact
o Through secreting mitochondrial derived vesicles
o Through metabolites and release of other signalling molecules
CROSS TALK WITH OTHER ORGANELLES
- Mitochondria can directly…
the nucleus, ER, peroxisome, lipid droplet, and endolysosome.
CROSS TALK WITH OTHER ORGANELLES
what contact is the best characterised
the mito-ER contact
CROSS TALK WITH OTHER ORGANELLES
Mito-ER contact sites (MERCS)
MERCS are specialised regions where the outer mitochondrial membrane (OMM) is closely apposed (10–30 nm) to the ER membrane, without fusing.
These contact sites are highly dynamic, and not random — they are stabilised by tethering proteins.
MERCS are communication hubs. They allow rapid and local signalling between mitochondria and the ER, coordinating energy production, lipid metabolism, cell death, and stress responses.
CROSS TALK WITH OTHER ORGANELLES
Mito-ER contact sites (MERCS): FUNCTION
Calcium signaling
The ER releases Ca²⁺ through IP₃ receptors into mitochondria at MERCS.
CROSS TALK WITH OTHER ORGANELLES
Mito-ER contact sites (MERCS): FUNCTION
Lipid exchange
Transfer of phospholipids like phosphatidylserine (PS) and phosphatidylethanolamine (PE).
CROSS TALK WITH OTHER ORGANELLES
Mito-ER contact sites (MERCS): FUNCTION
Mitochondrial dynamics
MERCS help define fission sites by recruiting Drp1 and ER tubules wrap around mitochondria.
CROSS TALK WITH OTHER ORGANELLES
Mito-ER contact sites (MERCS): FUNCTION
Bioenergetics regulation
Ca²⁺ uptake stimulates TCA cycle enzymes, increasing ATP production.
CROSS TALK WITH OTHER ORGANELLES
Mito-ER contact sites (MERCS): FUNCTION
Apoptosis regulation
Excess Ca²⁺ transfer can trigger mitochondrial permeability and cytochrome c release.
CROSS TALK WITH OTHER ORGANELLES
Mito-ER contact sites (MERCS): FUNCTION
Autophagy initiation
MERCS are proposed as a platform for autophagosome formation.
CROSS TALK WITH OTHER ORGANELLES
Mito-lysosome contact
- Mitochondria also have direct contact with lysosomes.
Mito-lysosome contact sites are regions where mitochondria and lysosomes come into close proximity (~10–30 nm) without fusing. These contacts are stable, regulated, and serve distinct functions from mitophagy.
CROSS TALK WITH OTHER ORGANELLES
Mito-lysosome contact: FUNCTION
- This mediates calcium, cholesterol, and iron transfer between the two organelles.
- Mito-lysosome contact sites can simultaneously regulate both mitochondrial and lysosome dynamics, including mitochondrial fission events and lysosomal tethering.
- As lysosomes are central hubs for nutrient storage and release, while mitochondria are essential for energy production, the mito-lysosome interactions can affect cellular health, energy balance, and the overall homoestasis of the cell.
CROSS TALK WITH OTHER ORGANELLES
Mito-lysosome contact: FUNCTION
Calcium exchange
Lysosomes can serve as Ca²⁺ sources; Ca²⁺ is transferred to mitochondria to regulate metabolism.
CROSS TALK WITH OTHER ORGANELLES
Mito-lysosome contact: FUNCTION
Cholesterol and lipid transfer
Lipid exchange helps maintain membrane composition and energy balance.
CROSS TALK WITH OTHER ORGANELLES
Mito-lysosome contact: FUNCTION
Iron homeostasis
Iron released from lysosomes can be delivered to mitochondria for heme synthesis and iron-sulfur clusters.
CROSS TALK WITH OTHER ORGANELLES
Mito-lysosome contact: FUNCTION
Fission regulation
These contact points can help coordinate mitochondrial fission alongside ER contacts.
CROSS TALK WITH OTHER ORGANELLES
Mito-lysosome contact: FUNCTION
Lysosome positioning
Mitochondria help anchor or traffic lysosomes within the cell via motor proteins.
CROSS TALK WITH OTHER ORGANELLES
Mito-lysosome contact: FUNCTION
Stress adaptation
Contacts help cells adapt to nutrient stress, oxidative stress, and mitochondrial dysfunction.
CROSS TALK WITH OTHER ORGANELLES
Mito-lysosome contact: KEY PROTEINS
Rab7: Small GTPase that regulates both lysosome transport and mitophagy; also tethers mitochondria and lysosomes.
TBC1D15/TBC1D17: Rab7 GTPase-activating proteins located on mitochondria.
RILP: Interacts with Rab7 and VDAC to maintain the contact.
LAMTOR proteins: Found on lysosomes, help coordinate signaling at the contact site.
CROSS TALK WITH OTHER ORGANELLES
Mito-lipid dropet contact
- Mito-lipid drop contact is another example, which are mediated by a number of tethering proteins.
- These contact sites facilitate the exchange of lipids, such as free fatty acids and cholesterol, between the two organelles,
o enabling mitochondria to utilise fatty acids from LDs as substrates for β-oxidation and ATP production. - Conversely, mitochondria can supply ATP and acetyl-CoA for lipid droplet formation and remodelling.
o This dynamic interplay helps cells adapt to metabolic demands and stress conditions, such as starvation, by mobilising energy reserves.
CROSS TALK WITH OTHER ORGANELLES
Mito-lipid dropet contact
chatgpt
These are direct contact sites where the outer mitochondrial membrane is closely apposed to the surface of lipid droplets (LDs) — dynamic fat-storing organelles.
Unlike passive diffusion, these contact sites facilitate active exchange of lipids and metabolites to balance energy demand and lipid homeostasis.
CROSS TALK WITH OTHER ORGANELLES
Mito-lipid dropet contact: FUNCTIONS
Lipid transfer
Free fatty acids (FFAs) move from LDs to mitochondria for β-oxidation and ATP production.
CROSS TALK WITH OTHER ORGANELLES
Mito-lipid dropet contact: FUNCTIONS
Energy buffering
During starvation or high energy demand, mitochondria rapidly access stored lipids.
CROSS TALK WITH OTHER ORGANELLES
Mito-lipid dropet contact: FUNCTIONS
Lipid droplet formation
Mitochondria supply ATP and acetyl-CoA needed for LD synthesis/remodelling.
CROSS TALK WITH OTHER ORGANELLES
Mito-lipid dropet contact: FUNCTIONS
Cholesterol and membrane regulation
Lipid shuttling influences mitochondrial membrane composition and function.
CROSS TALK WITH OTHER ORGANELLES
Mito-lipid dropet contact: FUNCTIONS
Stress response
Helps cells adapt to metabolic stress (e.g., fasting, cold, oxidative stress).
CROSS TALK WITH OTHER ORGANELLES
Mito-lipid dropet contact: KEY PROTEINS
PLIN5 (Perilipin 5): On LD surface, tethers mitochondria and facilitates fatty acid transfer.
SNAP23 and MFN2: Mediate contact stability and communication.
MIGA2: A mitochondrial outer membrane protein that links mitochondria to LDs in adipocytes.
DGAT enzymes: Involved in triacylglycerol synthesis at the contact site.
CROSS TALK WITH OTHER ORGANELLES
Mito-ER contact sites (MERCS): KEY PROTEINS
MFN2: Found on both mitochondria and ER; helps tether the two organelles.
IP₃ Receptor (IP₃R): Releases Ca²⁺ from ER.
VDAC (mitochondria) and Grp75 (linker): Help form a Ca²⁺ channeling complex.
PDZD8 (in mammals): Newly identified tethering protein.
Drp1: Fission protein recruited to MERCS.
CROSS TALK WITH OTHER ORGANELLES
Mitochondria derived vesicles
- mitochondria are capable of release specialized vesicle that target different compartments to allow cross-organelle interactions.
- These vesicles, known as MDVs (mitochondria-derived vesicles), are around 70–150 nm in diameter.
o They are generated under both normal and stress conditions.
CROSS TALK WITH OTHER ORGANELLES
Mitochondria derived vesicles
can exist as a…
single or double membraned entities, carrying diverse cargos, including proteins and lipids sourced from mitochondria.
- These vesicles are directed to different cellular compartments, serving versatile roles.
o For instance, they can be trafficked to lysosomes for degradation, effectively removing damaged mitochondrial components and preserving overall mitochondrial structure and function.
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Mitochondria derived vesicles: functions highlight
highlight the intricate integration of mitochondria into the cellular environment.
- transfer some cargo to peroxisome to promote peroxisome biogenesis.
- contribute to immune response, including presenting antigens derived from mitochondria to T cells to initiate adaptive immune responses and memory formation.
- aid the formation of phagophores that help the clearance of intracellular bacteria.
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Mitochondria derived vesicles:
chatgpt
MDVs are small membrane-bound vesicles (∼70–150 nm) that bud off from mitochondria and carry specific cargo (proteins, lipids, or damaged components) to other cellular compartments.
Unlike mitophagy (which degrades whole mitochondria), MDVs allow selective removal of damaged or unneeded mitochondrial parts without destroying the entire organelle.
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Mitochondria derived vesicles: Key Features
Formed under both normal and stress conditions
May contain outer membrane, inner membrane, or matrix-derived cargo
Generated independently of mitochondrial fission machinery (i.e., Drp1-independent)
Can be single or double-membraned, depending on their content and destination
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Mitochondria derived vesicles: functions
Lysosomes
Degradation of damaged mitochondrial proteins or lipids (quality control)
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Mitochondria derived vesicles: functions
Peroxisomes
Delivery of specific proteins/lipids to assist in peroxisome biogenesis
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Mitochondria derived vesicles: functions
Endosomes/Phagophores
Assist in antigen presentation and immune responses
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Mitochondria derived vesicles: functions
Cytosol/Plasma Membrane
May release mitochondrial components during stress or immune signaling
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Mitochondria derived vesicles: biological roles
Quality control: Remove oxidized or misfolded mitochondrial proteins
Immunity: Present mitochondrial antigens to T cells via MHC-I
Infection response: Aid in clearance of intracellular bacteria via phagophore formation
Metabolic adaptation: Adjust mitochondrial content based on nutrient status
Stress signaling: Deliver signals (e.g., mtDNA, ROS-regulated proteins)
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Mitochondria derived vesicles: importance
MDVs provide a precise and energy-efficient mechanism to maintain mitochondrial health and communicate with other organelles, making them key players in cellular homeostasis, innate immunity, and disease response.
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Mitochondrial metabolic signalling
- Mitochondria can also directly release metabolites and signalling molecules into cytoplasm to affect overall cellular activities.
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Mitochondrial metabolic signalling
example: citrate
citrate can be transported from the mitochondrial matrix to the cytoplasm,
where citrate is converted into cytosolic acetyl-CoA.
Inside mitochondria, acetyl-CoA serves as the starting substrate for the TCA cycle, playing a vital role in energy production.
In the cytoplasm, acetyl-CoA is utilized in lipid synthesis and protein acetylation.
One significant function of acetyl-CoA is its role in histone acetylation, which modifies chromatin structure to promote the transcription of nuclear genes, linking mitochondrial metabolism to the regulation of gene expression.
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Mitochondrial metabolic signalling
example: cytochrome c
o Cytochrome c released from mitochondria will activate caspases, a family of killer proteases, to trigger apoptosis.
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Mitochondrial metabolic signalling
example: mtDNA
o mtDNA can also be released from mitochondria.
That triggers cGAS-Sting pathway and inflammasome to modulate immune responses.
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Mitochondrial metabolic signalling
what insights
Understanding these mechanisms provides insights into the broader implications of mitochondrial metabolic signaling in cellular homeostasis and disease pathogenesis.
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Mitochondrial metabolic signalling
what
Mitochondrial metabolic signalling refers to the process by which metabolites, cofactors, and signalling molecules produced by mitochondria influence cell function, including:
Gene expression
Cell fate decisions
Stress responses
Immunity and inflammation
Key Signalling Molecules from Mitochondria
Acetyl-CoA
Used in lipid synthesis and histone acetylation, regulating gene expression
Key Signalling Molecules from Mitochondria
Citrate
Exported to cytoplasm → source of acetyl-CoA and regulator of lipid synthesis
Key Signalling Molecules from Mitochondria
ROS (e.g. H₂O₂)
At low levels: signalling. At high levels: oxidative stress → apoptosis
Key Signalling Molecules from Mitochondria
NAD⁺ / NADH
Regulate enzymes like sirtuins and PARPs → impact on metabolism, aging
Key Signalling Molecules from Mitochondria
Succinate / Fumarate
Stabilize HIF-1α → hypoxia signalling; may activate inflammation
Key Signalling Molecules from Mitochondria
mtDNA fragments
Activate innate immune sensors (e.g. cGAS-STING, inflammasomes)
Key Signalling Molecules from Mitochondria
Cytochrome c
Triggers apoptosis by activating caspases
Mitochondrial metabolic signalling
why is it important
Mitochondrial metabolic signalling:
Coordinates cellular energy status with gene regulation and biosynthetic needs
Influences stem cell differentiation, immune responses, and epigenetics
Plays a role in disease (e.g., cancer, neurodegeneration, metabolic disorders)
Mitochondrial metabolic signalling
example pathways:
Acetyl-CoA and Epigenetics:
Mitochondrial citrate → cytosol → converted to acetyl-CoA → histone acetylation → gene activation.
Mitochondrial metabolic signalling
example pathways:
ROS and Cell Fate:
Mitochondrial ROS activate signaling pathways like MAPK, NF-κB, or apoptosis via cytochrome c release.
Mitochondrial metabolic signalling
example pathways:
mtDNA as DAMPs:
Mitochondrial damage → release of mtDNA into cytoplasm → triggers innate immunity via cGAS-STING.
