ROMO1 and mitochondrial complex II/SDH are required for spare respiratory capacity and glucose homeostasis in mice

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.

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/ROMO1.

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 which catalyse mitochondrial inner and outer membrane fusion. Knockout of Romo1 in adult pancreatic beta cells results in impaired glucose homeostasis in young male mice (4 months) 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 Romo1 adult beta cell knockout (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 of ROMO1 in isolated human islets reduced spare respiratory capacity, which involved the specific loss of respiratory activity at complex II/succinate dehydrogenase. Ageing of female RABKO mice resulted in loss of spare respiratory capacity and glucose intolerance.

Our data demonstrate that ROMO1 is a key regulator of mitochondrial bioenergetics and spare respiratory capacity 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 euglycaemia and to the potential for targeting ROMO1/complex II to promote glucose coupling in settings of insulin insufficiency.