OMA1 mediates OPA1 proteolysis and mitochondrial fragmentation in experimental models of ischemic kidney injury

Xiao, Xiao; Hu, Yanzhong; Quirós, Pedro M.; Wei, Qingqing; López-Otı́n, Carlos; Dong, Zheng

doi:10.1152/ajprenal.00036.2014

Cited by 101 publications

(92 citation statements)

References 36 publications

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“…Remarkably, when L-OPA1 was genetically preserved by the additional deletion of Oma1, tissue atrophy was reduced in both models and this correlated with a significant improvement in fitness and prolonged lifespan. In another study, Oma1-knockout mice were shown to have improved renal function after ischemic kidney injury, an acute insult that also promotes OPA1 processing (Xiao et al, 2014). These reports therefore demonstrate that the suppression of OMA1 is protective in pathological models that are caused by persistent mitochondrial stress.…”

Section: Mitochondrial-dysfunction-induced Opa1 Processing Causes Celmentioning

confidence: 78%

OPA1 processing in cell death and disease – the long and short of it

MacVicar

Langer

2016

Journal of Cell Science

369

318

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The regulation of mitochondrial dynamics by the GTPase OPA1, which is located at the inner mitochondrial membrane, is crucial for adapting mitochondrial function and preserving cellular health. OPA1 governs the delicate balance between fusion and fission in the dynamic mitochondrial network. A disturbance of this balance, often observed under stress and pathologic conditions, causes mitochondrial fragmentation and can ultimately result in cell death. As discussed in this Commentary, these morphological changes are regulated by proteolytic processing of OPA1 by the inner-membrane peptidases YME1L (also known as YME1L1) and OMA1. Long, membrane-bound forms of OPA1 are required for mitochondrial fusion, but their processing to short, soluble forms limits fusion and can facilitate mitochondrial fission. Excessive OPA1 processing by the stress-activated protease OMA1 promotes mitochondrial fragmentation and, if persistent, triggers cell death and tissue degeneration in vivo. The prevention of OMA1-mediated OPA1 processing and mitochondrial fragmentation might thus offer exciting therapeutic potential for human diseases associated with mitochondrial dysfunction.

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Section: Mitochondrial-dysfunction-induced Opa1 Processing Causes Celmentioning

confidence: 78%

OPA1 processing in cell death and disease – the long and short of it

MacVicar

Langer

2016

Journal of Cell Science

369

318

View full text Add to dashboard Cite

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“…[1][2][3] Excessive oxidative stress, apoptosis, epithelial and endothelial cell dysfunction, and inflammation are among the important pathophysiologic mechanisms during ischemic AKI. [4][5][6][7] Recent work demonstrates an important pathophysiologic role for T lymphocytes in AKI, but the underlying mechanisms are poorly understood. [8][9][10][11] Traditional mechanisms of immune activation and responses through allo-or self-antigen are not known to occur during AKI.…”

mentioning

confidence: 99%

T Lymphocyte–Specific Activation of Nrf2 Protects from AKI

Noel¹,

Martina

Bandapalle³

et al. 2015

Journal of the American Society of Nephrology

101

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T lymphocytes are established mediators of ischemia reperfusion (IR)-induced AKI, but traditional immune principles do not explain their mechanism of early action in the absence of alloantigen. Nrf2 is a transcription factor that is crucial for cytoprotective gene expression and is generally thought to have a key role in dampening IRinduced AKI through protective effects on epithelial cells. We proposed an alternative hypothesis that augmentation of Nrf2 in T cells is essential to mitigate oxidative stress during IR-induced AKI. We therefore generated mice with genetically amplified levels of Nrf2 specifically in T cells and examined the effect on antioxidant gene expression, T cell activation, cytokine production, and IR-induced AKI. T cell-specific augmentation of Nrf2 significantly increased baseline antioxidant gene expression. These mice had a high frequency of intrarenal CD25 increased T cell expression of Nrf2 were significantly protected from functional and histologic consequences of AKI. Furthermore, adoptive transfer of high-Nrf2 T cells protected wild-type mice from IR injury and significantly improved their survival. These data demonstrate that T cell-specific activation of Nrf2 protects from IR-induced AKI, revealing a novel mechanism of tissue protection during acute injury responses.

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“…Loss of OMA1 protects cultured cells against apoptosis (Head et al, 2009;Quirós et al, 2012;Jiang et al, 2014;Xiao et al, 2014). We have previously described that apoptosis contributes to neuronal loss in Phb2 NKO mice, but have detected only a limited number of TUN EL-positive neurons (Merkwirth et al, 2012).…”

Section: Oma1 Deletion Protects Phb2-deficient Cells Against Apoptosismentioning

confidence: 99%

“…Oma1-deficient mice exhibit impaired thermogenesis and diet-induced obesity (Quirós et al, 2012). Moreover, loss of OMA1 in cultured cells was found to protect against apoptosis (Head et al, 2009;Quirós et al, 2012;Jiang et al, 2014;Xiao et al, 2014). However, the general in vivo relevance of stress-induced OPA1 processing by OMA1, and in particular its importance for neuronal survival, is not understood.…”

Section: Introductionmentioning

confidence: 99%