TY - JOUR
T1 - OPA1 Isoforms in the Hierarchical Organization of Mitochondrial Functions
AU - Del Dotto, Valentina
AU - Mishra, Prashant
AU - Vidoni, Sara
AU - Fogazza, Mario
AU - Maresca, Alessandra
AU - Caporali, Leonardo
AU - McCaffery, J. Michael
AU - Cappelletti, Martina
AU - Baruffini, Enrico
AU - Lenaers, Guy
AU - Chan, David
AU - Rugolo, Michela
AU - Carelli, Valerio
AU - Zanna, Claudia
N1 - Ricercatore distaccato presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Carelli Valerio)
PY - 2017/6/20
Y1 - 2017/6/20
N2 - 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.
AB - 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.
KW - dominant optic atrophy
KW - mitochondrial network dynamics
KW - mtDNA
KW - OPA1 isoforms
KW - OPA1 long-short form balance
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U2 - 10.1016/j.celrep.2017.05.073
DO - 10.1016/j.celrep.2017.05.073
M3 - Article
C2 - 28636943
AN - SCOPUS:85020889519
VL - 19
SP - 2557
EP - 2571
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 12
ER -