Mitochondria Flashcards
Mitochondrial dysfunction in neurodegenerative disorders
- maybe due to direct effects in mitochondrial proteins/quality control failures
- sometimes secondary to oxidative stress, protein aggregation
- always leads to increased oxidative stress and decreased energy (inefficient ATP production)
Role of mit
- Production of NADH and energy (ATP)
- Production of metabolites
- Ca2+ storage organelles
- Production of ROS
- Initiator of the apoptotic cascade
Positive roles of mit
- Production of NADH and energy (ATP)
- Production of metabolites necessary for cell function
- Ca2+ storage organelles (esp in neurons to prevent calcium build-up)
BAD effects of mit
- Production of ROS
5. Initiator of the apoptotic cascade
Mitochondria balance between ___ & _____
fission and fusion
Proteins involved in mitochondrial fusion:
- Mitofusin (Mfn) 1 and 2
- Optic atrophy (OPA) 1
Proteins involved in mitochondrial fission:
- Fis 1
- Dynamin-related protein (Drp) 1
- Endophilin B1
Fusion
stimulated by energy demand and stress
Fission
generates new organelles and facilitates quality control
allows mit trafficking w/in the cell
Normal mit look like ____
in absence of fission they look like ____
in absence of fusion looks like ____
WORMS
no fission = dense reticulum –concentrated/mit can’t localize properly (won’t get mit to periphery of cell)
no fusion = dots–looks very fragmented
At any time in the cells there is a mix of ____ & ____ mitochondria, due to the balance between ____ & ______
elongated & short;
fusion & fission
Mitochondrial dynamics
- Fragmentation facilitates recruitment of mitochondria to cellular compartments in need of ATP (axon terminals, dendrites)
- Mitochondrial fusion may represent a way to cope with “stress” and mtDNA mutations
- Increased fusion of mitochondria inhibit/retard apoptosis
- Apoptosis is normally associated with mitochondria fission
role of mit fragmentation
Fragmentation facilitates recruitment of mitochondria to cellular compartments in need of ATP (axon terminals, dendrites)
Apoptosis is normally associated with ____ (fusion vs. fission)
FISSION
increased fusionPREVENTS apoptosis
Mitochondrial defects mainly affect tissues with…
Mitochondrial defects mainly affect tissues with high energy demand
(nervous system, skeletal muscle)
Pathologies associated with mtDNA
mutations
Mitochondrial encephalomyopathies
mix of neurological and myopathic symptoms: myoclonic seizures, ataxia, muscle weakness
Pathologies associated Mitochondria
damage/dysfunction
PD, AD, HD, ALS
Pathologies associated Aberrant mitochondria dynamics (transport,
fusion/fission)
- Charcot-Marie-Tooth type 2A (CMT2A)–classical axon-sensory motor neuropathy
- Dominant Optic Atrophy (bilateral degeneration of optic nerve), other peripheral neuropathy
- And PD, AD, HD, ALS
Mit fusion allows
coping with stress
fusion leads to mixing of Mit DNA will compensate for deficits
Mit dysfunction in AD
-The activity of the mitochondrial respiratory chain is impaired in AD
brains and fibroblasts from patients.
-Oxidative damage is an early event in AD and increases production of
A-beta
Mit dysfunction in PD
-Toxins that inhibit complex I induce Parkinson, and complex I
dysfunction is observed in PD patients and animal models.
- Reduction of coenzyme Q (essential cofactor for mit function) levels in PD brain and peripheral cells
- Many proteins implicated in the development of PD (parkin, PINK1, DJ-1,
etc.) are involved in mitophagy and affect mitochondrial functions.
In PD and AD neurons, mitochondrial DNA accumulates more mutations
than in normal cells. WHY?
mit dysfunction –> ox stress –> further damage and dysfunction
_______ has also been proposed as a potential mechanism
underlying mitochondrial dysfunctions in neurodegenerative diseases such
as AD, HD and PD.
Altered mitophagy
Leads to the accumulation of dysfunctional mitochondria in neurons
Mit dysfunction in HD
- Impaired ability to store Ca++ . Mitochondria depolarization occurs at lower Ca++ concentration than normal
- Leakage of cytochrome c
- Increased mitochondrial fission
- Impaired mitochondrial import
- Decreased activity of mitochondrial Complexes II and III and decreased production of ATP
Mit dysfunction in ALS
- Mitochondria are profoundly impaired in familial and sporadic forms of
ALS - Mutant SOD1 localizes to mitochondria in affected cells and induces mitochondrial vacuolar degeneration BEFORE motoneurons start dying (alters protein import)
- Mutant TDP43 associates with mitochondria and affects the transcription
of complex I subunits (alters the ability of mit to store Calcium)
Therapeutic approaches that target mitochondria
- Compounds that inhibit mitochondrial fission
- ## Bioenergetic compounds
Compounds that inhibit mitochondrial fission
Mdivi-1
Bioenergetic compounds
- Creatine
- Coenzyme Q and derivatives
Mitochondria-targeted antioxidants
- MitoQ and related molecules
- Szeto-Schiller peptide (SS-31)
Mdivi-1–Cytoprotection
- dependent on Drp1
- inhibits Bax/Bak-mediated apoptosis
- activates AKT and ERk1/2 pathways (pro-survival pathways)
- reduces ROS
Mdivi-1–Cytotoxic
- Independent of Drp1
- impairs DNA replication
- induces G2/M cell cycle arrest
Critique of Mdivi-1
- Specificity for Drp1 inhibition has been recently questioned because
of its high Ki. - Alternative mechanisms might be responsible for its neuroprotective effects.
Biogenic compounds efficacy
Bioenergetic compounds that improve mitochondrial function and ATP
availability have shown promising results in models and are/have been in
clinical trials for PD, HD and AD
Creatine
- a crucial energy reservoir for ATP (esp in tissues with high energy demand–msucles and NS)
- It is part of the creatine/phosphocreatine system and plays an
important role in maintaining energy balance in brain and muscle
and buffering ATP levels.
2 creatine kinases
- mitochondrial creatine kinase (miCK) converts creatine to phosphocreatine (converts ATP –> ADP)
- Cytosolic creatine kinase (cCK) converts dephosphorylates phosphocreatine (produces ATP)
Phoscreatine–use
Phosphocreatine functions as a SPATIAL energy buffer
between the cytosol and mitochondria
Dephosphorylation releases ATP
Creatine neuroprotection
Neuroprotection might be mediate by:
“ increased availability of cytosolic ATP
“ inhibition of the mitochondrial permeability transition pore
Extensively tested in PD and HD, with disappointing results. Large
phase III trials halted because of lack of effects. A trial in ALS still
ongoing.
CoenzymeQ role in mitochondria
- essential cofactor of electron transport chain
- accepts electrons from complex I & II transfers them to complex III
CoenzymeQ10
Ubiquinone (oxidized form)
Ubiquinol (reduced form)
CoenzymeQ10: as a treatment
- Potent anti-oxidant in the inner mitochondrial membranes
- Anti-apoptotic: it blocks BAX association with mitochondria and inhibits
mitochondrial permeability transition pore. - Extensively tested in various trials in PD and HD. No effects.
Coenzyme Q10 therapeutic failure
failed to have effects in huge trails for PD and HD
may lie in CoQ10’s inability to easily cross the BBB, cell memb and mit memb
use Idebenone, MitoQ instead
Idebenone
synthetic, more soluble analogue of CoenzymeQ10 (can get into brain, cells and mit more easily)
Idebenone–efficacy
- number of clinical trials have shown significant benefits in AD patients
(improvement in ADAS, memory and attention, slower progression of cognitive
deficit). In clinical trial for AD. - Failed to be effective in a small clinical trial for HD.
- Studies have shown only a small fraction of the drug reaches mitochondria
MitoQ
- Attachment of a lipophilic TPP to coenzyme Q favors accumulation of the compound in the mitochondria
- (+) charge of TPP gets drawn into (-) charged mit matrix
- Once in the cell MitoQ is rapidly reduced to the active quinol form by the
respiratory system. - MitoQ insertion in the mitochondrial membrane ensures protection of mitochondrial lipids and membrane proteins from oxidative damage.
TPP conjugation
adding a lipophilic triphenyl-phosphonium group to increase accumulation of the drug in the mitochondria
- used for CoQ10, Vitamin E, SOD
- TPP-conjugated antioxidants have been developed (MitoVitE and MitoSOD)
MitoQ downsides
independent study indicated that MitoQ could lead to the death of kidney cells
- causing swelling/fragmentation of mit and depolarization –> apoptosis
MitoQ for neurological and
neurodegenerative diseases
- Phase II double-blind clinical trial in PD patients in New Zealand showed no
improvement observed over one year–likely too late in disease progression to help - Authors suggested it might be too late for improvement in symptomatic PD
patients. - BUT MitoQ might still slow down disease progression over longer
periods (used early to slow disease progression) - Ongoing trials for fibromyalgia, chronic fatigue syndrome and for fatigue in
multiple sclerosis All showing beneficial effects. - BBB penetration might be an issue (b/c it is a substrate of p-glycoprotein and Bcrp)
Szeto-Schiller peptide (SS-31)
- Structural motif with 4 alternating aromatic (T and F) and basic ( R and K)
amino acids (aromatic-cationic peptides). - The amino acid sequence of these peptides allows them to freely penetrate
cells and to be targeted to the mitochondria, where they accumulate. - The antioxidant action is attributed to the tyrosine residue, which can
scavenge oxyradicals.
Szeto-Schiller peptide (SS-31)–clincial use
Pharmacokinetic studies suggest SS-31 can cross the BBB
In clinical trial for cardioprotection after heart attack (tradename:
Bendavia)
Szeto-Schiller peptide (SS-31) mit entry
Independent of membrane potential (not due to charge of SS31)
Mediated by binding to cardiolipin (phospholipid only present on mit membrane)
