MTFP1 controls mitochondrial fusion to regulate inner mitochondrial membrane quality control and maintain mtDNA levels

Mitochondrial dynamics regulate cell fate and control mtDNA levels and distribution, but the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation are unclear. We show that the inner mitochondrial membrane (IMM) protein Mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Altering MTFP1 levels modulates mtDNA CN. MTFP1 controls mitochondrial fusion to isolate damaged IMM subdomains, segregating them into small mitochondria targeted for autophagic degradation. MTFP1-dependent IMM quality control is crucial for nucleoid recycling and maintaining adequate mtDNA levels. To understand how MTFP1 selects mtDNA molecules for recycling, we deep-sequenced WT and MTFP1-KO U2OS cells and found no differences in the burden of mitochondrial single nucleotide variants (mtSNVs) or heteroplasmy levels between WT and MTFP1-KO cells, indicating that MTFP1-driven mtDNA turnover does not differentiate between mtDNA alleles.