Amino Acids Promote Mitochondrial-Derived Compartment Formation in Mammalian Cells

Abstract

SUMMARYWe recently identified a new cellular structure in yeast, called the Mitochondrial-Derived Compartment (MDC), that forms on mitochondria in response to amino acid excess. While emerging evidence supports an important function for MDCs in protecting cells from metabolic stress, whether this system exists beyond yeast remains unclear. Here, we show that MDCs are conserved in mammals, and like their yeast counterparts, are responsive to the intracellular amino acid content. Specifically, we find that inhibition of protein translation stimulates formation of dynamic, micron-sized compartments that associate with the mitochondrial network. These compartments are enriched for the carrier receptor Tomm70A and other select mitochondrial outer and inner membrane cargo, associate with the ER membrane, and require the conserved GTPase Miro1 for formation. Mammalian MDCs are responsive to changes in amino acid levels during translation inhibition, and are not activated by other common cellular stressors. Thus, MDCs represent an evolutionarily conserved nutrient-responsive mitochondrial remodeling system.

VPS13D bridges the ER to mitochondria and peroxisomes via Miro

“…Swelling of mitochondria, in turn, may impair the action of the fission machinery. Interestingly, it was reported that, in mammalian cells, expansion of the so-called “mitochondrial derived compartment,” a newly described membranous organelle derived from the OMM, requires Miro and contacts between mitochondria and the ER, consistent with a role of Miro in a process that may involve lipid flux from the ER ( English et al, 2020 ; Schuler et al, 2020 Preprint ).…”

Mitochondria shed their outer membrane in response to infection-induced stress

“…The large diameter and lack of mitochondrial matrix proteins in SPOTs suggested that they differed from fragmented mitochondria as well as mitochondria-derived compartments (MDCs) and mitochondria-derived vesicles (MDVs), which form in response to amino acid toxicity and oxidative stress, respectively (14)(15)(16)(17)(18)(19). MDCs average 1 mm in diameter and depend on the OMM guanosine triphosphatase (GTPase) MIRO1 (mitochondrial rho GTPase 1), which mediates mitochondrial trafficking (16,17).…”

Human CCDC51 and yeast Mdm33 are functionally conserved mitochondrial inner membrane proteins that demarcate a subset of organelle fission events

“…BFP-OMP25 and mCherry- OMP25 were generated by cloning the OMP25 cassette from GFP-OMP25 into the XhoI/BamHI sites of pTagBFP-C and pmCherry-C1, respectively. TIMM50-GFP was generated by PCR amplifying the TIMM50 cassette from pLenti-mTIMM50-mRFP (a gift of Adam Hughes; (Schuler et al, 2020)) and cloning into the XhoI/BamHI sites of pAcGFP1-N1. TIMM50-mCherry was subsequently generated by digesting the mCherry cassette from pmCherry-N1 and cloning into the BamHI/NotI sites of TIMM50-GFP.…”