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. 2022 Dec 7;12(12):220274. doi: 10.1098/rsob.220274

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© 2022 The Authors.

Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

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Figure 4. — Regulators of mitochondrial fission and fusion and secondary mitochondrial disease. Mitochondrial fusion events occur by successive fusion of outer and inner membranes. Mitochondrial fusion GTPases MFN1 and MFN2 mediate OM fusion in conjunction with MSTO1, a cytosolic accessory protein recruited to the OM via an unknown mechanism. Mitochondrial IM fusion is coordinated by balanced processing of the OPA1 GTPase from long-form (L-OPA1) into short-form (S-OPA1). L-OPA1 can form oligomers and promote fusion upon GTP hydrolysis. Excessive L-OPA1 processing into S-OPA1 can disrupt L-OPA1 fusion events and tip the balance towards mitochondrial network fission. Mitochondrial fission is an essential component in cellular proliferation and is also used to clear terminally damaged or toxic nodes from the network via mitophagy. Fission factors such as MFF, MIEF1 and MIEF2 recruit cytosolic GTPase DNM1L to the OM, where it assembles in a spiral formation to restrict mitochondria and sever the double membrane upon GTP hydrolysis. DNM1L GTPase activity is dynamically controlled via a number of post translational modifications, including phosphorylation as mediated by kinases such as STAT2. GDAP1 is another fission factor localized to the OM. While loss of GDAP1 prevents efficient mitochondrial fission, the exact role of GDAP1 in cooperation with other OM fission mediators is yet to be uncovered. Within the mitochondrial contact site and cristae organizing system (MICOS) only two components have been connected to secondary mitochondrial disease: CHCHD10 and MICOS13. MICOS13 is an IM scaffolding protein required for the integration of other MICOS members into the mature complex. CHCHD10 is an IMS protein peripherally associated with the MICOS and is believed to maintain complex stability. Gene names are boxed, and associated diseases are listed below or indicated here: CHCHD10 (IMMD (MIM #616209), SMAJ (MIM #615048) and FTDALS2 (MIM #615911)); DNM1L (EMPF1 (MIM #614388)); GDAP1 (CMT2K (MIM #607831) and CMT4A (MIM #214400)); MFF (EMPF2 (MIM #617086)); MFN2 (CMT2A2A (MIM #609260), CMT2A2B (MIM #617087) and HMSN6A (MIM #601152)); MICOS13 (COXPD37 (MIM #618329)); MIEF2 (COXPD49 (MIM #619024)); MSTO1 (MMYAT (MIM #617675)); OPA1 (MTDPS14 (MIM #616896), BEHRS (MIM #210000) and OPA1 (MIM #165500)); STAT2 (IMD44 (MIM #616636) and PTORCH3 (MIM #618886)).