The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover

Xu, Shan; Peng, Guihong; Wang, Yan; Fang, Shengyun; Karbowski, Mariusz

doi:10.1091/mbc.e10-09-0748

Cited by 221 publications

(218 citation statements)

References 46 publications

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“…The proteasome is also recruited to these depolarized mitochondria. This is consistent with recent studies that p97 (also known as valosin-containing protein, VCP) can be recruited to mitochondria and is involved in OMM protein degradation (41,42). Massive degradation or specific degradation of some critical protein(s) causes OMM rupture, which would trigger degradation of intermembrane space proteins.…”

Section: Discussionsupporting

confidence: 92%

Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane

Yoshii

Kishi

Ishihara

et al. 2011

Journal of Biological Chemistry

544

463

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Upon mitochondrial depolarization, Parkin, a Parkinson disease-related E3 ubiquitin ligase, translocates from the cytosol to mitochondria and promotes their degradation by mitophagy, a selective type of autophagy. Here, we report that in addition to mitophagy, Parkin mediates proteasome-dependent degradation of outer membrane proteins such as Tom20, Tom40, Tom70, and Omp25 of depolarized mitochondria. By contrast, degradation of the inner membrane and matrix proteins largely depends on mitophagy. Furthermore, Parkin induces rupture of the outer membrane of depolarized mitochondria, which also depends on proteasomal activity. Upon induction of mitochondrial depolarization, proteasomes are recruited to mitochondria in the perinuclear region. Neither proteasome-dependent degradation of outer membrane proteins nor outer membrane rupture is required for mitophagy. These results suggest that Parkin regulates degradation of outer and inner mitochondrial membrane proteins differently through proteasome-and mitophagydependent pathways.Parkinson disease is a progressive neurodegenerative disease that is characterized by postural changes, resting tremor, muscle rigidity, and weakness (1, 2). These symptoms are mainly caused by loss of dopaminergic neurons in the substantia nigra, and mitochondrial dysfunction appears to be the primary pathogenic event. Indeed, many of the products of Parkinson disease-related genes such as ␣-synuclein/PARK1/4, PARKIN/ PARK2, PINK1/PARK6, DJ-I/PARK7, and OMI/HTRA2 are physically and functionally linked to mitochondria (3,4).Parkin is a RING domain-containing E3 ubiquitin ligase, and its mutation causes autosomal recessive juvenile Parkinson disease (5). Recent studies have revealed that Parkin is important for mitochondrial quality control through degradation of damaged mitochondria. Narendra et al. (6) first demonstrated that Parkin translocates from the cytosol to depolarized mitochondria and triggers elimination of these mitochondria by autophagy, which is known as mitophagy. Targeting of Parkin to mitochondria requires PTEN-induced putative kinase 1 (Pink1), 3 another Parkinson disease-associated gene product (7-14). Pink1 is an extremely unstable mitochondrial protein, but it is stabilized upon mitochondrial depolarization and subsequently recruits Parkin.Autophagy is a membrane-mediated intracellular degradation process. A portion of cytoplasm is first enclosed by the double-membraned autophagosome, and the autophagosome then fuses with a lysosome to degrade the enclosed materials. Although autophagy has been thought to be mainly non-selective, recent studies have revealed that the autophagosomal membrane can recognize some specific proteins and organelles. Parkin-mediated autophagy of damaged mitochondria is one of the best examples of selective autophagy. However, the precise role of Parkin in the induction of mitophagy has not been fully elucidated. To date, several mitochondrial proteins, voltage-dependent anion channel 1 (VDAC1) (8), mitofusin (a mitochondrial pro-fusion factor)...

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Section: Discussionsupporting

confidence: 92%

Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane

Yoshii

Kishi

Ishihara

et al. 2011

Journal of Biological Chemistry

544

463

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“…These extracted proteins are then degraded by the UPS. Along with mitofusins, the anti-apoptotic BCL-2 family member protein MCL-1 is extracted from the OMM for UPS dependent degradation by VCP/p97 once ubiquitylated [55].…”

Section: Outer Mitochondrial Membrane Fission and Fusionmentioning

confidence: 99%

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Ali

McStay

2017

Preprint

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The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as ATP synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space. Mitochondrial fission and fusion are performed by GTPases on the outer and inner mitochondrial membranes with the assistance of other mitochondrial proteins. Due to the essential nature of mitochondrial function for cellular homeostasis regulation of mitochondrial dynamics is under strict control. Some of the mechanisms used to regulate the function of these proteins are post-translational proteolysis and/or turnover and this review will discuss these mechanisms required for correct mitochondrial network organization. IntroductionMitochondria are the power houses of every nucleated cell, generating chemical energy in the form of adenosine triphosphate (ATP) by the oxidative phosphorylation (OXPHOS) system. Mitochondria are also important for the normal functioning of the cells as they regulate several crucial activities like differentiation, cell cycle, intracellular signaling and cell death [1]. Mitochondria are unique because of their autonomous DNA (mtDNA), which encodes for proteins required for ATP synthesis. Therefore maintenance of mtDNA is important for normal mitochondrial function and for the diversity of mitochondrial genome [2]. Mitochondria form elongated tubules that continually divide and fuse to form a complex, interconnected and highly dynamic network inside of cells. These dynamics processes not only regulate mitochondrial function but also mitochondrial shape, content exchange and mitochondrial communication with the cytoskeleton [3]. Due to the involvement of mitochondria in a large spectrum of cellular functions, these organelles play a key role in mediating cellular homeostasis. As a result a healthy population of mitochondria is critical for cell survival.

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“…Given that BCS1 was seen to be stably expressed over normal development (Fig. 7) but has been shown to be among the most stress-inducible transcripts encoding mitochondrial proteins (Van Aken et al, 2009), it may have a more specific role in the repair of proteins following a wide variety of stresses (Xu et al, 2011).…”

Section: Aaa-type Atpasesmentioning

confidence: 99%

Multiple Lines of Evidence Localize Signaling, Morphology, and Lipid Biosynthesis Machinery to the Mitochondrial Outer Membrane of Arabidopsis

et al. 2011

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The composition of the mitochondrial outer membrane is notoriously difficult to deduce by orthology to other organisms, and biochemical enrichments are inevitably contaminated with the closely associated inner mitochondrial membrane and endoplasmic reticulum. In order to identify novel proteins of the outer mitochondrial membrane in Arabidopsis (Arabidopsis thaliana), we integrated a quantitative mass spectrometry analysis of highly enriched and prefractionated samples with a number of confirmatory biochemical and cell biology approaches. This approach identified 42 proteins, 27 of which were novel, more than doubling the number of confirmed outer membrane proteins in plant mitochondria and suggesting novel functions for the plant outer mitochondrial membrane. The novel components identified included proteins that affected mitochondrial morphology and/or segregation, a protein that suggests the presence of bacterial type lipid A in the outer membrane, highly stress-inducible proteins, as well as proteins necessary for embryo development and several of unknown function. Additionally, proteins previously inferred via orthology to be present in other compartments, such as an NADH: cytochrome B5 reductase required for hydroxyl fatty acid accumulation in developing seeds, were shown to be located in the outer membrane. These results also revealed novel proteins, which may have evolved to fulfill plant-specific requirements of the mitochondrial outer membrane, and provide a basis for the future functional characterization of these proteins in the context of mitochondrial intracellular interaction.

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The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover

Cited by 221 publications

References 46 publications

Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane

Parkin Mediates Proteasome-dependent Protein Degradation and Rupture of the Outer Mitochondrial Membrane

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Multiple Lines of Evidence Localize Signaling, Morphology, and Lipid Biosynthesis Machinery to the Mitochondrial Outer Membrane of Arabidopsis

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