ROMO1 Is an Essential Redox-Dependent Regulator of Mitochondrial Dynamics

Norton, Matthew; Ng, Andy Cheuk-Him; Baird, Stephen; Dumoulin, Ariane; Shutt, Timothy E.; Mah, Nancy; Andrade‐Navarro, Miguel A.; McBride, Heidi M.; Screaton, Robert A.

doi:10.1126/scisignal.2004374

Cited by 111 publications

(124 citation statements)

References 66 publications

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“…Fusion is induced by oxidized glutathione 77,78 and regulated by the redox-sensing protein ROMO1. 79 Fusion, and the consequent sharing of antioxidant defense, is considered a protective response to oxidative stress, preserving mitochondrial redox balance. 78,80 Indeed, mitochondrial fragmentation is associated with increased mitochondrial ROS levels, conversely tubular morphology prevents ROS production.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

et al. 2016

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Pathological mutations in the mitochondrial DNA (mtDNA) produce a diverse range of tissue-specific diseases and the proportion of mutant mitochondrial DNA can increase or decrease with time via segregation, dependent on the cell or tissue type. Previously we found that adenocarcinoma (A549.B2) cells favored wild-type (WT) mtDNA, whereas rhabdomyosarcoma (RD.Myo) cells favored mutant (m3243G) mtDNA. Mitochondrial quality control (mtQC) can purge the cells of dysfunctional mitochondria via mitochondrial dynamics and mitophagy and appears to offer the perfect solution to the human diseases caused by mutant mtDNA. In A549.B2 and RD.Myo cybrids, with various mutant mtDNA levels, mtQC was explored together with macroautophagy/autophagy and bioenergetic profile. The 2 types of tumor-derived cell lines differed in bioenergetic profile and mitophagy, but not in autophagy. A549.B2 cybrids displayed upregulation of mitophagy, increased mtDNA removal, mitochondrial fragmentation and mitochondrial depolarization on incubation with oligomycin, parameters that correlated with mutant load. Conversely, heteroplasmic RD.Myo lines had lower mitophagic markers that negatively correlated with mutant load, combined with a fully polarized and highly fused mitochondrial network. These findings indicate that pathological mutant mitochondrial DNA can modulate mitochondrial dynamics and mitophagy in a cell-type dependent manner and thereby offer an explanation for the persistence and accumulation of deleterious variants.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

et al. 2016

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“…Electron microscopy and insulin immunogold labelling Pancreases were fixed in 2.6% glutaraldehyde overnight and processed as described previously [29] (ESM Methods).…”

Section: Methodsmentioning

confidence: 99%

LKB1 couples glucose metabolism to insulin secretion in mice

Robitaille

Faubert

et al. 2015

Diabetologia

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Aims/hypothesis Precise regulation of insulin secretion by the pancreatic beta cell is essential for the maintenance of glucose homeostasis. Insulin secretory activity is initiated by the stepwise breakdown of ambient glucose to increase cellular ATP via glycolysis and mitochondrial respiration. Knockout of Lkb1, the gene encoding liver kinase B1 (LKB1) from the beta cell in mice enhances insulin secretory activity by an undefined mechanism. Here, we sought to determine the molecular basis for how deletion of Lkb1 promotes insulin secretion. Methods To explore the role of LKB1 on individual steps in the insulin secretion pathway, we used mitochondrial functional analyses, electrophysiology and metabolic tracing coupled with by gas chromatography and mass spectrometry. Results Beta cells lacking LKB1 surprisingly display impaired mitochondrial metabolism and lower ATP levels following glucose stimulation, yet compensate for this by upregulating both uptake and synthesis of glutamine, leading to increased production of citrate. Furthermore, under low glucose conditions, Lkb1 −/− beta cells fail to inhibit acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in lipid synthesis, and consequently accumulate NEFA and display increased membrane excitability. Conclusions/interpretation Taken together, our data show that LKB1 plays a critical role in coupling glucose metabolism to insulin secretion, and factors in addition to ATP act as coupling intermediates between feeding cues and secretion. Our data suggest that beta cells lacking LKB1 could be used as a system to identify additional molecular events that connect metabolism to cellular excitation in the insulin secretion pathway.

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“…ROMO1 also has been shown to affect cells through oxidative stress-induced proliferation, apoptosis, and senescence (Na et al 2008;Shin et al 2013;Chung et al 2008). In the January 2014 issue of Science Signaling, Norton et al (2014) in the cristae and mitochondrial fusion is dependent on optic atrophy 1 (OPA1), a guanosine triphosphatase (GTPase) (Chung et al 2006) (Fig. 1).…”

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confidence: 99%