Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells

Head, Brian; Griparić, Lorena; Amiri, Mojgan; Gandre-Babbe, Shilpa; Bliek, Alexander M. van der

doi:10.1083/jcb.200906083

Cited by 447 publications

(517 citation statements)

References 19 publications

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“…OPA1 was silenced only partially (to~60%) to observe mild phenotypes, as stronger OPA1 knockdown would itself induce mitophagy and apoptosis, independent of CCCP. [25][26][27] The data confirm that expression of w/t NDPK-D increases CCCP-induced CL externalization. This increase occurred under both conditions, control and OPA1 silenced, but was more statistically significant (Po0.01 versus 0.05) in OPA1-silenced cells.…”

Section: Resultssupporting

confidence: 69%

“…OPA1, beyond its classical role in inner membrane fusion, 41,42 is also directly implicated in mitochondrial quality control via its stressregulated proteolytic cleavage via OMA1. 25,26,43 In functional mitochondria, OPA1/NDPK-D interaction helps to fuel OPA1 with GTP, 44 but this topology has to be different from the one where NDPK-D is cross-linking the two mitochondrial membranes, which is kinase inactive. 7 Thus, OPA1/NDPK-D complex formation may have a role in determining NDPK-D function, and two pieces of evidence in HeLa cells support this idea.…”

Section: Discussionmentioning

confidence: 99%

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NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

Kagan¹,

Jiang²,

Huang³

et al. 2016

Cell Death Differ

162

133

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Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified as a mitophageal signal recognized by the microtubuleassociated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission-fusion dynamics in mitophagy regulation.

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Section: Resultssupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

Kagan¹,

Jiang²,

Huang³

et al. 2016

Cell Death Differ

162

133

View full text Add to dashboard Cite

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“…The autophagosome fuses with the lysosome forming an autolysosome in which the mitochondrial cargo is degraded with the mitochondrial reticulum, the depolarized daughter mitochondrion is unlikely to undergo fusion and is often degraded through mitophagy. Depolarization causes the loss of Opa1 54 and Mitofusins (Mfn1 and 2), [55][56][57] proteins necessary for the fusion of the inner and outer membranes of mitochondria, and thereby promotes mitochondrial fragmentation. In agreement with the essential role of fission in mitophagy, a yeast genetic screen revealed that Dnm1, the yeast homolog of Drp1, is essential for mitophagy.…”

Section: Modulation Of Mitochondrial Dynamics Before the Onset Of Mitmentioning

confidence: 99%

The pathways of mitophagy for quality control and clearance of mitochondria

2012

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Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration. Facts Mitophagy mediates clearance of damaged mitochondria, and is also involved in the removal of mitochondria from maturing erythrocytes and eliminating sperm-derived mitochondria after fertilization. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the core autophagic machinery to mitochondria for their selective removal. A pathway containing PTEN-induced putative protein kinase 1 (PINK1) and Parkin responds to loss of mitochondrial membrane potential by targeting damaged mitochondria for clearance. The PINK1/Parkin pathway is triggered when PINK1 is stabilized on the outer membrane of damaged mitochondria, where it facilitates recruitment of cytosolic Parkin. Damaged mitochondria are prevented from moving and fusing with the mitochondrial reticulum in preparation for their mitophagic clearance. Open QuestionsHow distinct are the mitophagy pathways triggered by different stimuli or conditions?To what extent does Parkin activate mitophagy by causing the degradation of mitochondrial surface proteins or hyperubiquitinating the mitochondrial surface? How do PINK1 and Parkin interact with one another and with substrates on the mitochondrial surface in causing mitophagy? In contrast to the remarkable conservation of the core autophagic machinery, why are mitophagy-specific genes so little conserved between yeast and mammals? How best should mitophagy be triggered by researchers probing physiologically relevant pathways?The mitochondrion is an important actor in the life of a eukaryotic cell, but, like all good actors, a mitochondrion needs to exit the stage at the right time. Mitophagy removes mitochondria once they have played their part. This artic...

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“…Oma1 is evolutionarily conserved and is also found in higher eukaryotes, although a role in turnover/processing of misfolded proteins substrates has not yet been assigned. Instead, mammalian OMA1 has been shown to be the protease responsible for induced cleavage of OPA1 and will be discussed in more detail later (Ehses et al 2009;Head et al 2009). Atp23 represents yet another conserved peptidase in the IM that may contribute to the maintenance of protein quality control.…”

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

Quality Control of Mitochondrial Proteostasis

Baker

Tatsuta²,

Langer

2011

Cold Spring Harbor Perspectives in Biology

225

193

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A decline in mitochondrial activity has been associated with aging and is a hallmark of many neurological diseases. Surveillance mechanisms acting at the molecular, organellar, and cellular level monitor mitochondrial integrity and ensure the maintenance of mitochondrial proteostasis. Here we will review the central role of mitochondrial chaperones and proteases, the cytosolic ubiquitin-proteasome system, and the mitochondrial unfolded response in this interconnected quality control network, highlighting the dual function of some proteases in protein quality control within the organelle and for the regulation of mitochondrial fusion and mitophagy.

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Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells

Abstract: A proteolytic cascade ensures that OMA1 cleaves and inactivates mitochondrial fusion protein OPA1 in times of stress, preventing damaged mitochondria from fusing with healthy organelles. (See also companion paper from Ehses et al. in this issue.)

Cited by 447 publications

References 19 publications

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

The pathways of mitophagy for quality control and clearance of mitochondria

Quality Control of Mitochondrial Proteostasis

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