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- Title
Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
- Authors
Hofstadter, William A.; Cook, Katelyn C.; Tsopurashvili, Elene; Gebauer, Robert; Pražák, Vojtěch; Machala, Emily A.; Park, Ji Woo; Grünewald, Kay; Quemin, Emmanuelle R. J.; Cristea, Ileana M.
- Abstract
The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases. During HCMV infection, mitochondrial progenies derived from peripheral fragmentation can be protected from mitophagy and result in elevated respiration through a mechanism leveraging ER-mitochondria and inter-mitochondria membrane contacts.
- Subjects
MITOCHONDRIAL dynamics; FISSION (Asexual reproduction); HUMAN cytomegalovirus; BIOENERGETICS; MITOCHONDRIA
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-51680-4