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P A Y W A L L E D S O U R C E : Mitochondion
Highlights
• Mitochondrial dysfunction plays a role in many human diseases and is a hallmark of aging.
• The precise mechanistic role of mitochondria in individual pathologies is often unclear.
• Mitochondria influence a diversity of cellular systems beyond energetics and ROS.
• Model organisms provide insight into the role of mitochondria in disease and longevity.
• Genetic diseases and GWAS provide insight into the role of mitochondria in human health.
Abstract
Mitochondria are eukaryotic organelles known best for their roles in energy production and metabolism. While often thought of as simply the ‘powerhouse of the cell,’ these organelles participate in a variety of critical cellular processes including reactive oxygen species (ROS) production, regulation of programmed cell death, modulation of inter- and intracellular nutrient signaling pathways, and maintenance of cellular proteostasis. Disrupted mitochondrial function is a hallmark of eukaryotic aging, and mitochondrial dysfunction has been reported to play a role in many aging-related diseases. While mitochondria are major players in human diseases, significant questions remain regarding their precise mechanistic role. In this review, we detail mechanisms by which mitochondrial dysfunction participate in disease and aging based on findings from model organisms and human genetics studies.
Outline
1. Introduction
2. Mitochondrial structure and organization
3. Mitochondrial genetics
3.1. Mitochondrial genome
3.2. Inheritance patterns
3.3. Polymorphisms and heteroplasmy
3.4. Environmental and age-related changes in heteroplasmy
3.5. Mitochondrial/nuclear compatibility
4. Mitochondrial metabolism
4.1. The electron transport chain
4.2. Mitochondrial membrane potential
4.3. Assessing function through membrane potential
4.4. TCA cycle dysfunction
4.5. A complicated relationship between respiration and age-related disease
4.6. Mitochondrial ROS
4.7. Complex I and NADH/NAD+
5. Mitochondrial dynamics and quality control
5.1. Fission and fusion
5.2. Mitophagy
5.3. Hormesis and retrograde signaling
5.4. Mitochondrial unfolded protein response
6. Human genetics
6.1. Variants of strong effects
6.2. Common variants - genome-wide association studies (GWAS)
6.3. GWAS evidence linking mitochondrial pathways to human disease
6.4. Endophenotypes
6.5. Additional evidence from GWAS
7. Discussion
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