biostudies-literaturePuri RIntramural NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke3645https://www.ebi.ac.uk/biostudies/studies/S-EPMC6692330biostudies-literatureUnknown10(1)Chronic mitochondrial stress associates with major neurodegenerative diseases. Recovering stressed mitochondria constitutes a critical step of mitochondrial quality control and thus energy maintenance in early stages of neurodegeneration. Here, we reveal Mul1-Mfn2 pathway that maintains neuronal mitochondrial integrity under stress conditions. Mul1 deficiency increases Mfn2 activity that triggers the first phasic mitochondrial hyperfusion and also acts as an ER-Mito tethering antagonist. Reduced ER-Mito coupling leads to increased cytoplasmic Ca²⁺ load that activates calcineurin and induces the second phasic Drp1-dependent mitochondrial fragmentation and mitophagy. Overexpressing Mfn2, but not Mfn1, mimics Mul1-deficient phenotypes, while expressing PTPIP51, an ER-Mito anchoringNature communicationsMul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts.PMC6692330NIH ZIA NS003029ZIA NS003029NIH ZIA NS002946ZIA NS002946Lin MYSheng ZHPuri RHuang NCheng XTfalseMul1 restrains Parkin-mediated mitophagy in mature neurons by maintaining ER-mitochondrial contacts.Chronic mitochondrial stress associates with major neurodegenerative diseases. Recovering stressed mitochondria constitutes a critical step of mitochondrial quality control and thus energy maintenance in early stages of neurodegeneration. Here, we reveal Mul1-Mfn2 pathway that maintains neuronal mitochondrial integrity under stress conditions. Mul1 deficiency increases Mfn2 activity that triggers the first phasic mitochondrial hyperfusion and also acts as an ER-Mito tethering antagonist. Reduced ER-Mito coupling leads to increased cytoplasmic Ca²⁺ load that activates calcineurin and induces the second phasic Drp1-dependent mitochondrial fragmentation and mitophagy. Overexpressing Mfn2, but not Mfn1, mimics Mul1-deficient phenotypes, while expressing PTPIP51, an ER-Mito anchoring2019-01-01T00:00:00Z2019 Aug2025-04-04T19:04:11.709Z2019-08-20T07:05:16ZS-EPMC66923303140978610.1038/s41467-019-11636-5