Mitochondrial Dysfunction

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title: Mitochondrial Dysfunction slug: mitochondrial-dysfunction category: hallmarks summary: Age-related decline in mitochondrial bioenergetics, biogenesis, and quality control, with downstream effects on ROS, inflammation, and cell death. lastUpdated: 2026-05-17 tags: [mitochondria, OXPHOS, ROS, mitophagy] references:

• "Sun, N., Youle, R. J. & Finkel, T. The mitochondrial basis of aging. Mol. Cell 61, 654–666 (2016)."

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What it is

Mitochondria generate ATP via oxidative phosphorylation, regulate apoptosis, synthesise haem and Fe–S clusters, and serve as signalling hubs. Aging reduces respiratory-chain efficiency, raises reactive-oxygen-species (ROS) leak, accumulates mitochondrial DNA mutations, and impairs the dynamics of mitochondrial fission, fusion, and mitophagy.

Why it matters in aging

Tissues with high energy demand — skeletal muscle, heart, brain — show the clearest functional decline tied to mitochondrial impairment. VO₂max (see VO2max biomarker) declines roughly 10% per decade after age 30, much of it traceable to mitochondrial capacity.

Mechanisms

• mtDNA mutations accumulate (mtDNA lacks histones and has limited repair).
• OXPHOS complex assembly drifts; super-complex stoichiometry changes.
• Mitophagy declines, retaining damaged mitochondria.
• mtUPR (unfolded protein response) signalling weakens.
• Inter-organelle contacts with the ER and lysosome become dysregulated.

What’s being studied

Zone-2 exercise and resistance training are the most reliable human interventions for improving mitochondrial capacity. NAD+ precursors, urolithin A, mitochondrial-targeted antioxidants (MitoQ, SS-31), and metformin all act on this axis with varying levels of human evidence.

Related entries

See also: Disabled macroautophagy, Exercise, VO2max.