The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency

Apr 9, 2026Nature communications

Stress response may reduce PINK1-related removal of damaged mitochondria by maintaining their protein import

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

The integrated stress response (ISR) regulates mitophagy by suppressing PINK1-dependent processes during various mitochondrial stress conditions.

The ISR maintains mitochondrial presequence protein import efficiency, which is crucial for mitochondrial health.
Increased protein synthesis without ISR can overwhelm mitochondrial import mechanisms, reducing import efficiency.
Pharmacological inhibition of protein synthesis can alleviate impairment in mitochondrial import.
Severe depolarizing stress leads to significant PINK1 accumulation even with an active ISR.
Mild mitochondrial stress allows for more efficient protein import when ISR is active, resulting in lower levels of mitophagy.
Compromised mitochondrial protein import without ISR leads to increased PINK1 accumulation, triggering mitophagy.

AI simplified

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.

Full Text

Full text is available at the source.

View full text (HTML) ↗

The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief