Characterization of OPA1 isoforms isolated from mouse tissues

Akepati, Vasudheva Reddy; Müller, Eva‐Christina; Otto, Albrecht; Strauss, Holger M.; Portwich, Michael; Alexander, Christiane

doi:10.1111/j.1471-4159.2008.05401.x

Cited by 100 publications

(69 citation statements)

References 51 publications

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“…In humans and mouse, OPA1 protein exists as a complex mixture of isoforms derived from its eight splice variants (46,(75)(76)(77). In our study, retroviral overexpression of OPA1 deacetylation mimic (K-to-R) isoforms could restore the basal OCR and mtDNA copy number of OPA-null cells but not the acetylation mimic (K-to-Q) mutants.…”

Section: Discussionmentioning

confidence: 57%

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SIRT3 Deacetylates and Activates OPA1 To Regulate Mitochondrial Dynamics during Stress

Samant

Zhang

Hong

et al. 2014

Molecular and Cellular Biology

365

267

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f Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. There is significant evidence suggesting a stringent association between morphology and bioenergetics of mitochondria. Morphological alterations in mitochondria are linked to several pathological disorders, including cardiovascular diseases. The consequences of stress-induced acetylation of mitochondrial proteins on the organelle morphology remain largely unexplored. Here we report that OPA1, a mitochondrial fusion protein, was hyperacetylated in hearts under pathological stress and this posttranslational modification reduced the GTPase activity of the protein. The mitochondrial deacetylase SIRT3 was capable of deacetylating OPA1 and elevating its GTPase activity. Mass spectrometry and mutagenesis analyses indicated that in SIRT3-deficient cells OPA1 was acetylated at lysine 926 and 931 residues. Overexpression of a deacetylation-mimetic version of OPA1 recovered the mitochondrial functions of OPA1-null cells, thus demonstrating the functional significance of K926/931 acetylation in regulating OPA1 activity. Moreover, SIRT3-dependent activation of OPA1 contributed to the preservation of mitochondrial networking and protection of cardiomyocytes from doxorubicin-mediated cell death. In summary, these data indicated that SIRT3 promotes mitochondrial function not only by regulating activity of metabolic enzymes, as previously reported, but also by regulating mitochondrial dynamics by targeting OPA1.

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Section: Discussionmentioning

confidence: 57%

“…S4A and B in the supplemental material). The OPA1-GED region, where these acetylated lysine residues are present, contains one of the coiled-coil domains necessary for the formation of homotypic complex between different OPA1 isoforms and is required for its role in mitochondrial fusion (15,46).…”

Section: Opa1 Is Acetylated At Lysmentioning

confidence: 99%

SIRT3 Deacetylates and Activates OPA1 To Regulate Mitochondrial Dynamics during Stress

Samant

Zhang

Hong

et al. 2014

Molecular and Cellular Biology

365

267

View full text Add to dashboard Cite

show abstract

“…In the mouse liver, only four Opa1 mRNAs are expressed, none of which encodes CTF-1 or -2 (23). Further, analysis of the murine genomic and EST databases did not show evidence of cryptic promoter(s) and alternative splicing sites that could justify the expression of these forms of Opa1.…”

Section: Resultsmentioning

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.

162

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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“…Mutations in OPA1 gene cause degeneration of retinal ganglion cells in autosomal dominant optic atrophy (55,56). Proteolytic processing of OPA1 splice variants, which are expressed in a tissue-specific manner (57,58), results in the accumulation of long and short OPA1 isoforms (58)(59)(60). Normal mitochondrial fusion depends on expression of both long and short OPA1 isoforms (59,61).…”

Section: Role Of Prohibitins In Cell Apoptosis and Atresiamentioning

confidence: 99%

The emerging roles of prohibitins in folliculogenesis

Thompson¹

2012

Front Biosci

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Prohibitins are members of a highly conserved eukaryotic protein family containing the stomatin/ prohibitin/flotillin/HflK/C (SPFH) domain [also known as the prohibitin (PHB) domain] found in divergent species from prokaryotes to eukaryotes. Prohibitins are found in unicellular eukaryotes, fungi, plants, animals and humans. Prohibitins are ubiquitously expressed and present in multiple cellular compartments including the mitochondria, nucleus, and the plasma membrane, and shuttles between the mitochondria, cytosol and nucleus. Multiple functions have been attributed to the mitochondrial and nuclear prohibitins, including cellular differentiation, anti-proliferation, and morphogenesis. In the present review, we focus on the recent developments in prohibitins research related to folliculogenesis. Based on current research findings, the data suggest that these molecules play important roles in modulating specific responses of granulose cells to follicle stimulating hormone (FSH) by acting at multiple levels of the FSH signal transduction pathway. Understanding the molecular mechanisms by which the intracellular signaling pathways utilize prohibitins in governing folliculogenesis is likely to result in development of strategies to overcome fertility disorders and suppress ovarian cancer growth. KeywordsProhibitins; PHB; PHB2; Repressor Of Estrogen Receptor Action; REA; mitochondria; nucleus; Review INTRODUCTIONUnderstanding the mechanisms underlying the growth and development of a competent follicle with the capacity to release a fertilizable oocyte is a major goal of reproductive biology, particularly, since female infertility is clearly a major public health issue. Ovarian granulosa cells (GCs) play an important physiological role in supporting the development and selection of the dominant follicle by controlling oocyte maturation and by producing the steroid hormones, estrogen (E 2 ) and progesterone (P 4 ) that are critical for maintenance of the ovarian cycle. Mammalian ovarian follicular development is tightly regulated by (1-6). Based on current research findings, the data suggest that these molecules play important roles in modulating specific responses of GCs to follicle stimulating hormone (FSH) by acting at multiple levels of the FSH signal transduction pathway. Understanding the molecular mechanisms by which the intracellular signaling pathways utilize prohibitins in governing folliculogenesis is likely to result in development of strategies to overcome fertility disorders and suppress ovarian cancer growth. In the last decade, significant progress has been made in analyzing the expression, distribution and in determining the specific roles that the PHB and REA play in mammalian reproductive physiology. In the present review, we summarize some of the recent developments in PHB and REA research related to folliculogenesis. PROHIBITINSProhibitins are members of an extensive evolutionarily conserved family of proteins which includes stomatins, plasma membrane proteins of Escherichia coli (HflKC), f...

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Characterization of OPA1 isoforms isolated from mouse tissues

Cited by 100 publications

References 51 publications

SIRT3 Deacetylates and Activates OPA1 To Regulate Mitochondrial Dynamics during Stress

SIRT3 Deacetylates and Activates OPA1 To Regulate Mitochondrial Dynamics during Stress

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

The emerging roles of prohibitins in folliculogenesis

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