Abstract
Mitochondrial dynamics and quality control have a central role in the maintenance of cellular integrity. Mitochondrial ubiquitin ligase membrane-associated RING-CH (MARCH5) regulates mitochondrial dynamics. Here, we show that mitochondrial adaptation to stress is driven by MARCH5-dependent quality control on acetylated Mfn1. Under mitochondrial stress conditions, levels of Mfn1 were elevated twofold and depletion of Mfn1 sensitized these cells to apoptotic death. Interestingly, overexpression of Mfn1 also promoted cell death in these cells, indicating that a fine tuning of Mfn1 levels is necessary for cell survival. MARCH5 binds Mfn1 and the MARCH5-dependent Mfn1 ubiquitylation was significantly elevated under mitochondrial stress conditions along with an increase in acetylated Mfn1. The acetylation-deficient K491R mutant of Mfn1 showed weak interaction with MARCH5 as well as reduced ubiquitylation. Neither was observed in the acetylation mimetic K491Q mutant. In addition, MARCH5-knockout mouse embryonic fibroblast and MARCH5H43W-expressing HeLa cells lacking ubiquitin ligase activity experienced rapid cell death upon mitochondrial stress. Taken together, a fine balance of Mfn1 levels is maintained by MARCH5-mediated quality control on acetylated Mfn1, which is crucial for cell survival under mitochondria stress conditions.
Highlights
The dynamic nature of mitochondria has a central role in preserving cellular homeostasis
We show that this MARCH5-dependent quality control on Mfn[1] is crucial for mitochondrial homeostasis and cell viability
We demonstrated a novel mitochondrial adaptation process mediated by two mitochondrial molecules, Mfn[1] and MARCH5
Summary
The dynamic nature of mitochondria has a central role in preserving cellular homeostasis. Parkin is recruited to the mitochondria with low mitochondrial membrane potential and subsequently ubiquitinates Mfn[1] and 2, triggering the elimination of impaired mitochondria.[25,26] A recent report identified the phosphorylated Mfn[2] as a Parkin receptor on damaged mitochondria.[27] the ubiquitylation–proteasome system in mitochondria contributes to mitochondrial dynamics and quality control, thereby having a central role in preserving cellular homeostasis. We discovered that MARCH5 serves as an upstream quality controller on Mfn[1], preventing excessive accumulation of Mfn[1] protein under stress conditions. We show that this MARCH5-dependent quality control on Mfn[1] is crucial for mitochondrial homeostasis and cell viability
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