IF systemic SkQ1 (5 nmol/kg/day via drinking water, 12 weeks) is administered to 22–24-month-old C57BL/6J mice of both sexes carrying the mito-QC mitophagy reporter transgene,

THEN a measurable reduction (≥20% decrease) in the fractional burden of large-scale mtDNA deletions across cardiac and skeletal muscle tissue will be observed at endpoint (week 12), accompanied by a ≥30% increase in basal mitophagic flux (mito-QC lysosomal:mitochondrial red-to-green puncta ratio) in the same tissues and normalization of lysosomal cathepsin B/D activity to levels observed in 6-month-old controls,

BECAUSE the following causal chain operates sequentially:

1. In aged mice (24 months), chronic mitochondrial ROS production generates lipid peroxidation products and protein carbonyls that accumulate as lipofuscin within lysosomes, physically and chemically inactivating cathepsins B, D, and L — the proteases required to degrade mitochondrial cargo delivered by completed mitophagosomes. This lysosomal blockade creates a downstream bottleneck that traps ubiquitinated, PINK1/Parkin-tagged damaged mitochondria in autolysosomes without degrading them, causing stalled mitophagic flux despite intact upstream recognition machinery. (Evidence: SkQ1 prevents lipofuscin formation and age-dependent autophagy decline by mitigating lipid peroxidation — Skulachev et al., Aging, 2017, cited in Evidence Set.)

2. Aged cardiac and hippocampal tissue show a precipitous decline in mitophagic flux relative to young controls, quantified using mito-QC and mt-Keima reporter systems; this decline is not attributable to failure of PINK1 stabilization or Parkin recruitment per se, but to failure of downstream lysosomal resolution — meaning already-accumulated heteroplasmic mtDNA-mutant mitochondria that are correctly flagged for removal cannot be degraded. (Evidence: McWilliams et al., Cell Metabolism, 2016; Sun et al., Molecular Cell, 2015, cited in Evidence Set.)

3. SkQ1, by accumulating electrochemically in the inner mitochondrial membrane (driven by membrane potential), quenches superoxide and lipid peroxyl radicals at their primary generation site — the respiratory chain — before they can diffuse to the lysosomal compartment. This selectively reduces the flux of oxidative species into lysosomes without globally suppressing mitochondrial membrane potential (which itself drives SkQ1 uptake), thereby protecting cathepsin activity. [SPECULATIVE: The spatial restriction of SkQ1 to the inner membrane means lysosomal ROS arising from non-mitochondrial sources may not be fully suppressed, so the effect is likely partial rather than complete cathepsin rescue.]

4. Restored lysosomal cathepsin activity re-enables completion of already-initiated but stalled mitophagy events — the bottleneck is cleared downstream, not upstream. This means mitochondria that have already been ubiquitinated, sequestered into autophagosomes, and fused with lysosomes but cannot be degraded are now processed, re...

SENS category: LysoSENS