ROMO1 and Mitochondrial Complex II/SDH are Required for Spare Respiratory Capacity and Glucose Homeostasis in Mice

Abstract Aims/Hypothesis Reactive oxygen species modulator 1 (ROMO1) is a highly conserved inner mitochondrial membrane protein that senses reactive oxygen species and regulates mitochondrial dynamics. ROMO1 is required for mitochondrial fusion in vitro , and silencing ROMO1 increases sensitivity to cell death stimuli. The physiological role of ROMO1 remains unclear. Methods To determine the role of ROMO1 in vivo , we used gene targeting in mice to ablate ROMO1 in the whole mouse and to conditionally knock out ROMO1 in the pancreatic beta cell. Mitochondrial functional analyses were performed on isolated mouse and human islets lacking ROMO1 . Results We show that ROMO1 is essential for embryonic development, as ROMO1-null mice die before embryonic day 8.5, earlier than GTPases OPA1 or MFN1/2 that catalyze mitochondrial inner and outer membrane fusion. Knockout of ROMO1 in adult pancreatic beta cells results in impaired glucose homeostasis in young male mice due to an insulin secretion defect. Isolated islets from male, but not female, mice showed impaired glucose-stimulated insulin secretion. While mitochondria from female mice were morphologically normal, mitochondria in R omo1 a dult b eta cell k nock o ut (RABKO) cells from male mice were swollen and fragmented, with a reduction in mtDNA content. Knockout of ROMO1 did not affect basal respiration in males or females, but deletion of ROMO1 in both sexes in mice and isolated human islets reduced spare respiratory capacity (SRC), which involved the specific loss of respiratory activity at Complex II/SDH. Aging of female ROMO1 KO mice resulted in loss of spare respiratory capacity and glucose intolerance. Conclusions/Interpretation Our data demonstrate that ROMO1 is a key regulator of mitochondrial bioenergetics and SRC and is required for effective nutrient coupling to insulin secretion in the beta cell. These observations point to a critical role for spare respiratory capacity in the maintenance of euglycemia and to the potential for targeting ROMO1-complex II to promote glucose coupling in settings of insulin insufficiency. Research in Context What is already known about this subject? ROMO1 is required for mitochondrial fusion Glucose coupling to insulin secretion is accomplished in part via generation of NADH during the oxidation of glycolytic metabolites in the TCA cycle Spare respiratory capacity is lost in aging What is the key question? What is the physiological role of ROMO1 in the whole animal and the pancreatic beta cell? What are the new findings? ROMO1 is essential for mouse development ROMO1 is required to maintain spare respiratory capacity (SRC) and to promote insulin secretion in the beta cells of mice and humans Ablation of the Romo1 gene in the pancreatic beta cell leads to glucose coupling defects and glucose intolerance in young males and aged females Aging highlights the importance of SRC in the beta cell for maintaining euglycemia How might this impact clinical practice in the foreseeable future? Aging is a significant risk factor for T2D. Human males, but not females, experience a loss of insulin secretion with age; designing strategies that enhance ROMO1 and complex II activity to promote SRC may help to reverse these effects.

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