The <i>i</i>-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission

Anand, Ruchika; Wai, Timothy; Baker, Michael J.; Kladt, Nikolay; Schauß, Astrid; Rugarli, Elena I.; Langer, Thomas

doi:10.1083/jcb.201308006

Cited by 623 publications

(722 citation statements)

References 52 publications

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“…11 OPA1 in complex with NME4/NDPK-D may retain the latter in the NDP kinase topology (Figure 1, left part). The cleavage of OPA1 by mitochondrial proteases, 51 which occurs directly after ΔΨ collapse and before execution of mitophagy, 52 may then weaken or even disrupt NME4/NDPK-D interaction with OPA1, thus releasing NME4/NDPK-D to crosslink MIM and MOM, and to engage into CL transfer (Figure 1, right part). These interpretations are still conjectural and need further experimental support.…”

Section: Nme4/ndpk-d In CL Signalingmentioning

confidence: 99%

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

Schlattner

Tokarska‐Schlattner

Epand

et al. 2018

Laboratory Investigation

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Mitophagy is an emerging paradigm for mitochondrial quality control and cell homeostasis. Dysregulation of mitophagy can lead to human pathologies such as neurodegenerative disorders and contributes to the aging process. Complex protein signaling cascades have been described that regulate mitophagy. We have identified a novel lipid signaling pathway that involves the phospholipid cardiolipin (CL). CL is synthesized and normally confined at the inner mitochondrial membrane. However, upon a mitophagic trigger, ie, collapse of the inner membrane potential, CL is rapidly externalized to the mitochondrial surface with the assistance of the hexameric nucleoside diphosphate kinase D (NME4, NDPK-D, or NM23-H4). In addition to its NDP kinase activity, NME4/NDPK-D shows intermembrane phospholipid transfer activity in vitro and in cellular systems, which relies on NME4/NDPK-D interaction with CL, CL-dependent crosslinking of inner and outer mitochondrial membranes by symmetrical, hexameric NME4/NDPK-D, and a putative NME4/NDPK-Dbased CL-transfer pathway. CL exposed at the mitochondrial surface then serves as an 'eat me' signal for the mitophagic machinery; it is recognized by the LC3 receptor of autophagosomes, targeting the dysfunctional mitochondrion to lysosomal degradation. Similar NME4-supported CL externalization is likely also involved in apoptosis and inflammatory reactions.

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Section: Nme4/ndpk-d In CL Signalingmentioning

confidence: 99%

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

Schlattner

Tokarska‐Schlattner

Epand

et al. 2018

Laboratory Investigation

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“…a loss of cristae (13). However, Opa1 function is complex and can also promote mitochondrial fragmentation (17). Upon mitochondrial dysfunction or depolarization, an inner membrane protease called Oma1 becomes activated, cleaving Opa1 into a short, soluble form that then promotes mitochondrial fragmentation (18,19).…”

Section: Significancementioning

confidence: 99%

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

Sood

Jeyaraju

Prudent

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

152

178

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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.T he last decade expanded our understanding of the importance of mitochondrial shape, position, and interorganellar interactions in the regulation of cell stress. For example, mitochondrial hyperfusion is a stress response that protects against cell death and autophagic degradation, whereas chronic stress triggers mitochondrial fragmentation and cell death. However, the in vivo implications of mitochondrial plasticity under normal physiological conditions are still largely unknown. The liver is a key organ responsible for nutrient sensing and the maintenance of wholebody energy homeostasis. Therefore, we considered the liver as a primary model to examine the changes in mitochondrial plasticity that accompanies physiological transitions in feeding and postprandial metabolism (1-4).The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionary conserved serine/threonine kinase that plays an important role in regulating metabolism and cell growth in response to anabolic signals (5). Studies indicate that mTORC1, which is activated by growth factors and amino acids, is a key sensor allowing cells and tissues to adapt their metabolism in response to the nutritional state (5). In the liver, it controls the activation of various metabolic proce...

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“…Western immunoblotting of the protein guanosine triphosphatase OPA1 demonstrated that long isoforms 1 and 2 (L1 and L2) and three short isoforms (S1, S2, and S3) (35) were detected in kidneys of WT and Aifm1…”

Section: Aif Knockdown Induces Mitochondrial Fusion Eventsmentioning

confidence: 99%

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

et al. 2016

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Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.

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The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission

Abstract: OPA1 processing by YEM1L and OMA1 is dispensable for mitochondrial fusion and instead drives mitochondrial fragmentation, which is crucial for mitochondrial integrity and quality control.

Cited by 623 publications

References 52 publications

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy

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

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

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