Mitochondrial morphology is regulated by RING domain proteins.

Mitochondrial morphology is shaped by ongoing fission and fusion of mitochondrial tubules. In mammalian cells, the large GTPase Drp1 is essential for mitochondrial fission while the GTPases Mfn1/2 and Opa1 are involved in mitochondrial fusion. A screen for mitochondrial morphogens encoded in the human genome revealed two novel RING domain containing proteins – MRP1 and MRP2. Since the RING domain is a hallmark of E3 ubiquitin ligases, we created dominant‐negative mutants of MRP1 and MRP2 by mutating conserved residues required for RING domain function. We found that inactivation of MRP1 by overexpression of the dominant‐negative mutant leads to elongation of mitochondria. Analysis of Drp1 localization revealed that inactive MRP1 locks Drp1 in seemingly unproductive mitochondrial fission complexes, thereby causing mitochondrial elongation through the inhibition of mitochondrial fission. In contrast, inactivation of MRP2 causes mitochondrial fragmentation. Since coexpression of Drp1 and inactive MRP2 greatly enhances this phenotype, we conclude that MRP2 may be involved in the regulation of mitochondrial fusion. Taken together, we have identified two putative E3 ubiquitin ligases antagonistically regulating mitochondrial fission and fusion, presumably by ubiquitination of key regulators of these opposing processes. These findings strongly suggest a previously unappreciated level of regulation of mitochondrial network dynamics in mammalian cells.