A Mitofusin-2-dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver

Aditi Sood, Danny Vijey Jeyaraju, Julien Prudent, Alexandre Caron, Philippe Lemieux, Heidi May McBride, Mathieu Laplante, Katalin Tóth, Luca Pellegrini

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Hepatic metabolism requires mitochondria to adapt their bioenergetic and biosynthetic output to accompany the ever-changing anabolic/catabolic state of the liver cell, but the wiring of this process is still largely unknown. Using a postprandial mouse liver model and quantitative cryo-EM analysis, we show that when the hepatic mammalian target of rapamycin complex 1 (mTORC1) signaling pathway disengages, the mitochondria network fragments, cristae density drops by 30%, and mitochondrial respiratory capacity decreases by 20%. Instead, mitochondria-ER contacts (MERCs), which mediate calcium and phospholipid fluxes between these organelles, double in length. These events are associated with the transient expression of two previously unidentified C-terminal fragments (CTFs) of Optic atrophy 1 (Opa1), a mitochondrial GTPase that regulates cristae biogenesis and mitochondria dynamics. Expression of Opa1 CTFs in the intermembrane space has no effect on mitochondria morphology, supporting a model in which they are intermediates of an Opa1 degradation program. Using an in vitro assay, we show that these CTFs indeed originate from the cleavage of Opa1 at two evolutionarily conserved consensus sites that map within critical folds of the GTPase. This processing of Opa1, termed C-cleavage, is mediated by the activity of a cysteine protease whose activity is independent from that of Oma1 and presenilin-associated rhomboid-like (PARL), two known Opa1 regulators. However, C-cleavage requires Mitofusin-2 (Mfn2), a key factor in mitochondria-ER tethering, thereby linking cristae remodeling to MERC assembly. Thus, in vivo, mitochondria adapt to metabolic shifts through the parallel remodeling of the cristae and of the MERCs via a mechanism that degrades Opa1 in an Mfn2-dependent pathway.

Original languageEnglish (US)
Pages (from-to)16017-16022
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number45
DOIs
StatePublished - Nov 11 2014
Externally publishedYes

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Autosomal Dominant Optic Atrophy
Mitochondria
Liver
GTP Phosphohydrolases
Presenilins
Cysteine Proteases
Organelles
Energy Metabolism
Phospholipids

Keywords

  • Mfn2
  • Mitochondria
  • Mitochondria-ER contacts
  • MTORC1
  • Opa1

ASJC Scopus subject areas

  • General

Cite this

A Mitofusin-2-dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver. / Sood, Aditi; Jeyaraju, Danny Vijey; Prudent, Julien; Caron, Alexandre; Lemieux, Philippe; McBride, Heidi May; Laplante, Mathieu; Tóth, Katalin; Pellegrini, Luca.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 45, 11.11.2014, p. 16017-16022.

Research output: Contribution to journalArticle

Sood, Aditi ; Jeyaraju, Danny Vijey ; Prudent, Julien ; Caron, Alexandre ; Lemieux, Philippe ; McBride, Heidi May ; Laplante, Mathieu ; Tóth, Katalin ; Pellegrini, Luca. / A Mitofusin-2-dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 45. pp. 16017-16022.
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abstract = "Hepatic metabolism requires mitochondria to adapt their bioenergetic and biosynthetic output to accompany the ever-changing anabolic/catabolic state of the liver cell, but the wiring of this process is still largely unknown. Using a postprandial mouse liver model and quantitative cryo-EM analysis, we show that when the hepatic mammalian target of rapamycin complex 1 (mTORC1) signaling pathway disengages, the mitochondria network fragments, cristae density drops by 30{\%}, and mitochondrial respiratory capacity decreases by 20{\%}. Instead, mitochondria-ER contacts (MERCs), which mediate calcium and phospholipid fluxes between these organelles, double in length. These events are associated with the transient expression of two previously unidentified C-terminal fragments (CTFs) of Optic atrophy 1 (Opa1), a mitochondrial GTPase that regulates cristae biogenesis and mitochondria dynamics. Expression of Opa1 CTFs in the intermembrane space has no effect on mitochondria morphology, supporting a model in which they are intermediates of an Opa1 degradation program. Using an in vitro assay, we show that these CTFs indeed originate from the cleavage of Opa1 at two evolutionarily conserved consensus sites that map within critical folds of the GTPase. This processing of Opa1, termed C-cleavage, is mediated by the activity of a cysteine protease whose activity is independent from that of Oma1 and presenilin-associated rhomboid-like (PARL), two known Opa1 regulators. However, C-cleavage requires Mitofusin-2 (Mfn2), a key factor in mitochondria-ER tethering, thereby linking cristae remodeling to MERC assembly. Thus, in vivo, mitochondria adapt to metabolic shifts through the parallel remodeling of the cristae and of the MERCs via a mechanism that degrades Opa1 in an Mfn2-dependent pathway.",
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AU - Prudent, Julien

AU - Caron, Alexandre

AU - Lemieux, Philippe

AU - McBride, Heidi May

AU - Laplante, Mathieu

AU - Tóth, Katalin

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