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Published June 20, 2017 | Published + Supplemental Material
Journal Article Open

OPA1 Isoforms in the Hierarchical Organization of Mitochondrial Functions

Abstract

OPA1 is a GTPase that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In humans, eight isoforms are expressed as combinations of long and short forms, but it is unclear whether OPA1 functions are associated with specific isoforms and/or domains. To address this, we expressed each of the eight isoforms or different constructs of isoform 1 in Opa1−/− MEFs. We observed that any isoform could restore cristae structure, mtDNA abundance, and energetic efficiency independently of mitochondrial network morphology. Long forms supported mitochondrial fusion; short forms were better able to restore energetic efficiency. The complete rescue of mitochondrial network morphology required a balance of long and short forms of at least two isoforms, as shown by combinatorial isoform silencing and co-expression experiments. Thus, multiple OPA1 isoforms are required for mitochondrial dynamics, while any single isoform can support all other functions. These findings will be useful in designing gene therapies for patients with OPA1 haploinsufficiency.

Additional Information

© 2017 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Published: June 20, 2017. This research was supported by grants from Ministero della Istruzione Università e Ricerca, MIUR (FIR2013 grant J38C13001770001 to C.Z. and PRIN grant 20107Z8XBW to M.R.), the NIH (grant GM110039 to D.C.), and E-Rare project 2009-ERMION to V.C., M.R., and G.L. V.D.D. was the recipient of a Marco Polo fellowship, University of Bologna.

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Published - PIIS2211124717307465.pdf

Supplemental Material - mmc1.pdf

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