Abstract
BackgroundMitochondrial dynamics is the result of a dynamic balance between fusion and fission events, which are driven via a set of mitochondria-shaping proteins. These proteins are generally considered to be binary components of either the fission or fusion machinery, but potential crosstalk between the fission and fusion machineries remains less explored. In the present work, we analyzed the roles of mitochondrial elongation factors 1 and 2 (MIEF1/2), core components of the fission machinery in mammals.ResultsWe show that MIEFs (MIEF1/2), besides their action in the fission machinery, regulate mitochondrial fusion through direct interaction with the fusion proteins Mfn1 and Mfn2, suggesting that MIEFs participate in not only fission but also fusion. Elevated levels of MIEFs enhance mitochondrial fusion in an Mfn1/2- and OPA1-dependent but Drp1-independent manner. Moreover, mitochondrial localization and self-association of MIEFs are crucial for their fusion-promoting ability. In addition, we show that MIEF1/2 can competitively decrease the interaction of hFis1 with Mfn1 and Mfn2, alleviating hFis1-induced mitochondrial fragmentation and contributing to mitochondrial fusion.ConclusionsOur study suggests that MIEFs serve as a central hub that interacts with and regulates both the fission and fusion machineries, which uncovers a novel mechanism for balancing these opposing forces of mitochondrial dynamics in mammals.
Highlights
Mitochondrial dynamics is the result of a dynamic balance between fusion and fission events, which are driven via a set of mitochondria-shaping proteins
In keeping with the results above, apart from the interaction with the pro-fission proteins dynamin-related protein 1 (Drp1), hFis1, and mitochondrial fission factor (Mff) as previously reported [25, 26, 29], we found that the key pro-fusion GTPases Mfn1 and Mfn2 were both coprecipitated efficiently with exogenously expressing MIEF1-V5 and MIEF2-V5 (Fig. 1a)
(See figure on previous page.) Fig. 1 Identification and characterization of binding regions in MIEFs required for Mfn1, Mfn2, hFis1, and Drp1. a Exogenous MIEF1-V5 and MIEF2-V5 interact with both pro-fission (Drp1, hFis1, Mff) and pro-fusion (Mfn1, Mfn2) proteins. 293T cells were transfected with empty vector, MIEF1V5, or MIEF2-V5 and were in vivo crosslinked with 1% formaldehyde (FA)
Summary
Mitochondrial dynamics is the result of a dynamic balance between fusion and fission events, which are driven via a set of mitochondria-shaping proteins. These proteins are generally considered to be binary components of either the fission or fusion machinery, but potential crosstalk between the fission and fusion machineries remains less explored. We analyzed the roles of mitochondrial elongation factors 1 and 2 (MIEF1/2), core components of the fission machinery in mammals. Mitochondria frequently change their morphology, size, and distribution via fission and fusion events to respond to altered metabolic demands or pathogenic assaults to the cell [1, 2]. Dynamin-related protein 1 (Drp1) together with Mff, MIEFs
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