Mitochondrial Disease

Question 1

Mitochondria Structure

Answer 1

• Cytoplasmic organelles in al nucleated cells
• Outer membrane permeable to small ions (H+) and inner membrane impermeable (so need transporters)
• Inner membrane invaginated –> inc SA for ETC and ATP synthase
• Tightly regulated fission and fusion
• Have own ribosomes so translation occurs inside mito itself

Question 2

Primary and Secondary Functions of Mitochondria (8)

Answer 2

Primary- oxidation of fuel molecules –> ATP
(pyruvate/FA –> acetyl CoA –> CO2 + electrons; electrons go into ETC –> water and electrochemical proton gradient outside inner membrane –> used to make ATP)

Secondary-

• ketogenesis (FA –> ketone bodies)
• urea cycle
• AA catabolism (AA broken down for energy)
• pyrimidine biosynthesis
• steroid and bile synthesis
• heme synthesis
• calcium homeostasis (synaptic transmission)
• apoptotic signaling (programmed cell death)

Question 3

Mitochondrial v Nuclear Genome

Answer 3

Mito - circular but still dbl stranded, no histones, much smaller, not paired (large and variable copy # 100-10000), higher mutation rate, maternal inheritance

Nuc- straight chromosomes, histones, larger, paired (copy # is 2)

Question 4

Heteroplasmy v homoplasmy

Answer 4

Hetero- cell that contains some normal mito DNA and some mutated

Homo- if all mito DNA in a cell have same sequence

Question 5

What does the mitochondrial genome code for?

Answer 5

-37 genes

• 2 make rRNA
• 22 make tRNA
• 13 code for proteins (all 13 proteins are part of ETC or ATP Synthase Complex)

Question 6

Why does mitochondrial DNA have higher mutation rate?

Answer 6

• less efficient DNA replication machinery
• less efficient DNA repair systems
• higher exposure to reactive oxygen species (ETC)

Question 7

Mitochondrial Inheritance Pattern

Answer 7

• Dad’s mito not in zygote (only mom)
• If mom is affected ALL children affected
• If dad is affected NO children affected

Question 8

Replicative Segregation

Answer 8

• During mitosis, daughter cells receive random sample of all the cell’s copies of DNA…so if heteroplasmic cell, ea daughter cell will get diff proportions of mutant and normal DNA
• In meiosis, diff oocytes can have very diff proportions (bottle neck effect)
• Leads to variable penetrance and expressivity in mito diseases
• Also means a person’s mito disease can vary in severity over life

Question 9

Threshold Effect

Answer 9

• Mutations tolerated up to a certain level (threshold)
• Due to replicative segregation, some cells in a person can be below threshold while others above OR moves above/below threshold during life span

Question 10

LHON

Answer 10

Leber hereditary optic neuropathy

Question 11

MELAS

Answer 11

mitochondrial encephalomyopathy lactic acidosis and stroke-like epsiodes

**pyruvate builds up, especially in brain

Question 12

MERRF

Answer 12

myoclonic epilepsy w/ ragged-red fibers

**mainly effects muscles and nervous system

Question 13

NARP

Answer 13

neuropathy, ataxia, and retinitis pigmentosa

Question 14

Leigh Disease

Answer 14

• severe neuro disorder that presents in first year and kids usually die in 2 or 3 years
• affect assembly of function of ETC
• SURF1 is common mutation