The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency - PubMed
4 hours ago
- #integrated stress response
- #mitochondrial import
- #mitophagy
- The integrated stress response (ISR) suppresses PINK1-dependent mitophagy by maintaining mitochondrial presequence protein import efficiency, independent of ATF4 activation.
- Without ISR, increased protein synthesis overwhelms mitochondrial import machineries, reducing import efficiency; this can be mitigated by inhibiting protein synthesis (e.g., with mTOR inhibitors).
- Under severe depolarizing stress, mitochondrial import is impaired even with ISR, leading to significant PINK1 accumulation and mitophagy.
- Under mild mitochondrial stress, ISR allows efficient protein import, resulting in lower mitophagy; without ISR, import is compromised, triggering PINK1 accumulation to mitophagy thresholds.
- The study links ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for mitochondrial dysfunction-related diseases.