Hypothesis

Mitochondrial ROS not only damages telomeres and epigenome but also induces chromosomal mosaicism in somatic cells by causing double‑strand breaks that escape repair, leading to persistent mCAs 1. These mCAs, in turn, alter expression of nuclear‑encoded mitochondrial genes, creating a feed‑forward loop that amplifies ROS production. Thus, mitochondrial dysfunction initiates a self‑reinforcing circuit where ROS‑generated mCAs worsen mitochondrial output, driving the concurrent emergence of genomic instability, senescence, epigenetic drift, and inflammation.

Testable predictions

1. Cells with induced mtDNA damage (e.g., via ethidium bromide or mito‑TALEN) will show a dose‑dependent increase in somatic mosaicism detectable by single‑cell DNA sequencing, and this increase will be attenuated by ROS scavengers such as MitoQ 2.

2. Single‑cell multi‑omics of aged hematopoietic stem cells will reveal that clones carrying specific mCAs exhibit downregulated expression of nuclear‑encoded mitochondrial respiratory chain genes (e.g., NDUFS1, COX4I1) and elevated mitochondrial ROS measured by MitoSOX 3.

3. CRISPR‑mediated correction of a representative mCA (e.g., loss of chromosome 8q) in hematopoietic progenitors will rescue mitochondrial gene expression and reduce ROS production, thereby delaying senescence markers (p16^INK4a^, SA‑β‑gal) in vitro 4.

4. In vivo, mice heterozygous for a PolG mutator phenotype that develop mtDNA damage will show accelerated accumulation of liver‑specific mCAs; treatment with a mitochondria‑targeted antioxidant will suppress both mCA burden and age‑related phenotypes (frailty, glucose intolerance) 5.

Falsifiability

If boosting mitochondrial ROS does not raise detectable mCAs, or if removing mCAs fails to improve mitochondrial function, the proposed loop is not supported. Conversely, a lack of correlation between mCA burden and mitochondrial gene expression in aged human tissues would refute the feed‑forward hypothesis 6.

Discussion

This hypothesis positions mitochondrial ROS as an upstream modulator that shapes the nuclear genome’s mosaicism landscape, linking the hallmark of genomic instability to the metabolic hallmarks. It extends ’s view by proposing that mCAs are not merely passive markers but active contributors to mitochondrial dysfunction, thereby converting a linear amplifier model into a bidirectional circuit.