A ULK1–MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis
Year: 2026
Type: article
Abstract: Mitophagy - the selective degradation of damaged mitochondria - preserves mitochondrial quality; yet, how mitochondrial fission is coordinated with autophagy initiation remains unclear. Here, we identified the mitochondrial outer membrane protein MTFR1L as a key component of mitophagy initiation hubs after using a synthetic FKBP-FRB system to tether ULK1 kinase to mitochondria independently of damage. We found that MTFR1L was enriched at ULK1 foci together with additional fission factors, and constitutive mitochondrial targeting of MTFR1L shifted mitochondrial morphology towards fragmentation. MTFR1L depletion decreased respiratory capacity, elevated apoptosis and impaired mitophagy flux. Upon mitophagy induction, MTFR1L was phosphorylated in a ULK1 kinase-dependent manner and reciprocally modulated ULK1 activity, establishing a feedback loop. Moreover, MTFR1L was required for proper ATG13 stability. These findings position MTFR1L as a critical link between mitochondrial fission and the autophagy machinery, coordinating mitophagy initiation and cell survival.
Source: Journal of Cell Science
DOI: 10.1242/jcs.264577
Institutions: University of Freiburg, Max Perutz Labs, Vienna Biocenter
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: DekonvolutionsMikroskop zur 4dimensionalen Lebendzellmikroskopie, G3775087215, EXC 2189: CIBSS Centre for Integrative Biological Signalling Studies, TIRF Superresolutionsmikroskop, SFB 1177: Molekulare und funktionale Charakterisierung der selektiven Autophagie, GRK 2606: Entschlüsselung zellulärer Proteasefunktionen durch Identifizierung und Analyse von Proteasesubstraten (ProtPath), SFB 1381: Dynamische Organisation zellulärer Proteinmaschinerien: Von der Biogenese und modularen Assemblierung zur Funktion
OpenAlex ID: W7154028602