Altered mitochondrial fusion drives defensive glutathione synthesis in cells able to switch to glycolytic ATP production

Patten, David A.; McGuirk, Shawn; Anilkumar, Ujval; Antoun, Ghadi; Gandhi, Karan; Parmar, Gaganvir; Iqbal, Mohamed Ariff; Wong, Jacob; Richardson, Richard B.; St‐Pierre, Julie; Slack, Ruth S.; Harper, Mary‐Ellen

doi:10.1016/j.bbamcr.2020.118854

Cited by 15 publications

(11 citation statements)

References 76 publications

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“…In addition, OPA1-MKO MuSCs had decreased gene expression of mtROS regulators SOD2 and UCP2 and increased levels of the redox marker SLC7a11 (Xct) (Figure 5B). Increased expression of SLC7a11, a direct target of the NRF2 redox response pathway for glutathione (GSH) biosynthesis (Shin et al, 2017), and a recent link between OPA1 and GSH (Patten et al, 2021) prompted further investigation. Expression of GSH synthetase (GSS) and glutamate cysteine ligase (GLCL) were upregulated in freshly isolated MuSCs from OPA1-MKO (Figure 5B).…”

Section: Disruption Of Opa1 and Mitochondrial Dynamics Alters The Qui...mentioning

confidence: 99%

The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells

et al. 2022

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Section: Disruption Of Opa1 and Mitochondrial Dynamics Alters The Qui...mentioning

confidence: 99%

The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells

et al. 2022

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“…Fused mitochondria exhibit an interconnected and networked structure. Mitochondrial over-fusion is associated with cancer biology and etiology ( 27 , 44 ). This dynamic procedure is performed by both outer and inner membranes, with outer membrane fusion mediated by the outer membrane protein, Mfn1/2, and inner membrane fusion mediated by the optic nerve atrophy protein, OPA1 ( 28 , 31 ) ( Table 1 ).…”

Section: Mitochondrial Dynamics and Cancersmentioning

confidence: 99%

Mitochondria-Shaping Proteins and Chemotherapy

et al. 2021

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The emergence, in recent decades, of an entirely new area of “Mitochondrial dynamics”, which consists principally of fission and fusion, reflects the recognition that mitochondria play a significant role in human tumorigenesis and response to therapeutics. Proteins that determine mitochondrial dynamics are referred to as “shaping proteins”. Marked heterogeneity has been observed in the response of tumor cells to chemotherapy, which is associated with imbalances in mitochondrial dynamics and function leading to adaptive and acquired resistance to chemotherapeutic agents. Therefore, targeting mitochondria-shaping proteins may prove to be a promising approach to treat chemotherapy resistant cancers. In this review, we summarize the alterations of mitochondrial dynamics in chemotherapeutic processing and the antitumor mechanisms by which chemotherapy drugs synergize with mitochondria-shaping proteins. These might shed light on new biomarkers for better prediction of cancer chemosensitivity and contribute to the exploitation of potent therapeutic strategies for the clinical treatment of cancers.

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“…An analysis of OPA1 mutated MEFs ranked the allele severity with the metabolic and lipid alterations, highlighting an increased spermine/spermidine ratio and a reduction in hydroxyproline, amino acid pool, and several phospholipids ( 65 ). Interestingly, the increase in glutathione in Opa1 null MEFs ( 63 ) has been recently confirmed in a second study ( 67 ) and reported, together with the increased dependency on cysteine transport, as a metabolic adaptive mechanism to afford protection against oxidative stress in these cells ( 67 ). Finally, this cell model has been also used for drug screening on amelioration of mitochondrial readouts with different missense mutations, proving to be a valuable tool in testing new DOA therapeutic interventions ( 45 ).…”

Section: Opa1 Cell Modelsmentioning

confidence: 69%

Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis

Dotto

Carelli

2021

Front. Neurol.

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In the year 2000, the discovery of OPA1 mutations as causative for dominant optic atrophy (DOA) was pivotal to rapidly expand the field of mitochondrial dynamics and describe the complex machinery governing this pathway, with a multitude of other genes and encoded proteins involved in neurodegenerative disorders of the optic nerve. OPA1 turned out to be a much more complex protein than initially envisaged, connecting multiple pathways beyond its strict role in mitochondrial fusion, such as sensing of OXPHOS needs and mitochondrial DNA maintenance. As a consequence, an increasing need to investigate OPA1 functions at multiple levels has imposed the development of multiple tools and models that are here reviewed. Translational mitochondrial medicine, with the ultimate objective of translating basic science necessary to understand pathogenic mechanisms into therapeutic strategies, requires disease modeling at multiple levels: from the simplest, like in yeast, to cell models, including the increasing use of reprogrammed stem cells (iPSCs) from patients, to animal models. In the present review, we thoroughly examine and provide the state of the art of all these approaches.

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Altered mitochondrial fusion drives defensive glutathione synthesis in cells able to switch to glycolytic ATP production

Cited by 15 publications

References 76 publications

The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells

The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells

Mitochondria-Shaping Proteins and Chemotherapy

Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis

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