Mitochondrial Dysfunction

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.

More on this topic

• Urolithin A — Intervention.
• Mitophagy (PINK1 / Parkin) — Pathway.
• Mitochondrial Theory of Aging — Theory.
• GDF-15 — Biomarker.
• Mitobridge (acquired by Astellas) — Company.

Related entries

See also: Disabled macroautophagy, Exercise, VO2max.