A proteomic screen with Drosophila Opa1-like identifies Hsc70-5/Mortalin as a regulator of mitochondrial morphology and cellular homeostasis

Banerjee, Shamik; Balaji, Chinthapalli

doi:10.1016/j.biocel.2014.05.041

Cited by 23 publications

(22 citation statements)

References 73 publications

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“…We also demonstrated that Mic60 overexpression suppresses mitochondrial fission and increases mitochondrial interconnectivity. This provides functional evidence associating Mic60 with regulation of mitochondrial dynamics, corroborating previous work describing protein interactions between Mic60/MICOS and mitochondrial dynamics proteins (Abrams et al, 2015; Banerjee and Chinthapalli, 2014; Darshi et al, 2011; Weihofen et al, 2009). Given the crucial role of Mic60 in maintaining mitochondrial architecture and function, our findings carry implications for the involvement of mitochondrial structural stability in PD.…”

Section: Discussionsupporting

confidence: 89%

“…Previous studies have found Mic60 protein interacts, both directly and indirectly, with proteins that regulate mitochondrial dynamics, including fusion protein OPA1 and the PD-linked protein PINK1 (Abrams et al, 2015; Banerjee and Chinthapalli, 2014; Darshi et al, 2011; Weihofen et al, 2009). Because dysregulation of mitochondrial dynamics has been increasingly linked to mechanisms of degeneration in PD models (Van Laar and Berman, 2013), we investigated whether the overexpression of Mic60 influenced cellular and neuritic mitochondrial fission and fusion dynamics.…”

Section: Resultsmentioning

confidence: 99%

“…Mounting evidence suggests MICOS participates in regulating mitochondrial dynamics. Previous studies have found that MICOS, and Mic60 specifically, interact with several proteins associated with mitochondrial dynamics (fusion protein OPA1, mitophagy-linked protein PINK1, and, via PINK1, the Miro/Milton mitochondrial transport complex; Abrams et al, 2015; Banerjee and Chinthapalli, 2014; Darshi et al, 2011; Weihofen et al, 2009). A recent study from Li et al also found that loss of Mic60 was associated with reduced fission and fusion rates in mouse embryonic fibroblasts (Li et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Mic60/mitofilin overexpression alters mitochondrial dynamics and attenuates vulnerability of dopaminergic cells to dopamine and rotenone

Laar

Berman

Hastings

2016

Neurobiology of Disease

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Mitochondrial dysfunction has been implicated in Parkinson’s disease (PD) neuropathology. Mic60, also known as mitofilin, is a protein of the inner mitochondrial membrane and a key component of the mitochondrial contact site and cristae junction organizing system (MICOS). Mic60 is critical for maintaining mitochondrial membrane structure and function. We previously demonstrated that mitochondrial Mic60 protein is susceptible to both covalent modification and loss in abundance following exposure to dopamine quinone. In this study, we utilized neuronally-differentiated SH-SY5Y and PC12 dopaminergic cell lines to examine the effects of altered Mic60 levels on mitochondrial function and cellular vulnerability in response to PD-relevant stressors. Short hairpin RNA (shRNA)-mediated knockdown of endogenous Mic60 protein in neuronal SH-SY5Y cells significantly potentiated dopamine-induced cell death, which was rescued by co-expressing shRNA-insensitive Mic60. Conversely, in PC12 and SH-SY5Y cells, Mic60 overexpression significantly attenuated both dopamine- and rotenone-induced cell death as compared to controls. Mic60 overexpression in SH-SY5Y cells was also associated with increased mitochondrial respiration, and, following rotenone exposure, increased spare respiratory capacity. Mic60 knockdown cells exhibited suppressed respiration and, following rotenone treatment, decreased spare respiratory capacity. Mic60 overexpression also affected mitochondrial fission/fusion dynamics. PC12 cells overexpressing Mic60 exhibited increased mitochondrial interconnectivity. Further, both PC12 cells and primary rat cortical neurons overexpressing Mic60 displayed suppressed mitochondrial fission and increased mitochondrial length in neurites. These results suggest that altering levels of Mic60 in dopaminergic neuronal cells significantly affects both mitochondrial homeostasis and cellular vulnerability to the PD-relevant stressors dopamine and rotenone, carrying implications for PD pathogenesis.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mic60/mitofilin overexpression alters mitochondrial dynamics and attenuates vulnerability of dopaminergic cells to dopamine and rotenone

Laar

Berman

Hastings

2016

Neurobiology of Disease

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“…This phenotype can be enhanced by increased mitochondrial fusion or ameliorated by overexpression of fission protein Drp1, demonstrating that directly or indirectly VDAC/PORIN function affects mitochondrial remodeling in flight muscles. Likewise, the fly chaperone Hsc70-5/Mortalin, related to the vertebrate Grp75, has been identified as a regulator of mitochondrial morphology and cellular homeostasis in a proteomic screen for OPA1 interactors [85]. Hsc70-5/Mortalin is an enhancer of OPA1 since its downregulation leads to phenotypes of fragmented mitochondria with reduced membrane potential.…”

Section: Mitochondrial Calcium Regulation In Aging Striated Musclementioning

confidence: 99%

Mitochondria in the Aging Muscles of Flies and Mice: New Perspectives for Old Characters

Campo

Jaimovich

Tevy

2016

Oxidative Medicine and Cellular Longevity

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Sarcopenia is the loss of muscle mass accompanied by a decrease in muscle strength and resistance and is the main cause of disability among the elderly. Muscle loss begins long before there is any clear physical impact in the senior adult. Despite all this, the molecular mechanisms underlying muscle aging are far from being understood. Recent studies have identified that not only mitochondrial metabolic dysfunction but also mitochondrial dynamics and mitochondrial calcium uptake could be involved in the degeneration of skeletal muscle mass. Mitochondrial homeostasis influences muscle quality which, in turn, could play a triggering role in signaling of systemic aging. Thus, it has become apparent that mitochondrial status in muscle cells could be a driver of whole body physiology and organismal aging. In the present review, we discuss the existing evidence for the mitochondria related mechanisms underlying the appearance of muscle aging and sarcopenia in flies and mice.

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“…Knocking in extra copies of a Caenorhabditis elegans homologue of mot-2 caused increase in their lifespan (19). These effects have been ascribed, in part, to the ability of mot-2 to (i) inactivate wild-type p53 functions including transcriptional activation (20,21), control of centrosome duplication (22), and deregulation of apoptosis in cancer cells (23)(24)(25); (ii) activate telomerase and hnRNP-K (26); (iii) and regulate oxidative stress (27,28) and mitochondrial structure (29,30). On the other hand, deficiency in mortalin has been well connected to the age-related pathologies including Alzheimer and Parkinson diseases (28,(31)(32)(33).…”

Section: Waf1mentioning

confidence: 99%

Functional Significance of Point Mutations in Stress Chaperone Mortalin and Their Relevance to Parkinson Disease

Wadhwa

Ryu

Ahn

et al. 2015

Journal of Biological Chemistry

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Background: Mortalin, an essential chaperone, is enriched in cancers; it possesses pro-proliferative and anti-apoptotic functions and has been found mutated in some Parkinson patients. Results: Mutant mortalins lack functions involved in carcinogenesis and cause increased oxidative stress; we demonstrate the factors and mechanism of their role in Parkinson disease. Conclusion: Mutations in mortalin contribute to Parkinson disease.Significance: This work contributes toward an understanding of mortalin-associated diseases for therapy.

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A proteomic screen with Drosophila Opa1-like identifies Hsc70-5/Mortalin as a regulator of mitochondrial morphology and cellular homeostasis

Cited by 23 publications

References 73 publications

Mic60/mitofilin overexpression alters mitochondrial dynamics and attenuates vulnerability of dopaminergic cells to dopamine and rotenone

Mic60/mitofilin overexpression alters mitochondrial dynamics and attenuates vulnerability of dopaminergic cells to dopamine and rotenone

Mitochondria in the Aging Muscles of Flies and Mice: New Perspectives for Old Characters

Functional Significance of Point Mutations in Stress Chaperone Mortalin and Their Relevance to Parkinson Disease

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