The cell biology of mitochondrial membrane dynamics

Harnessing the protective role of OPA1 in diabetic cardiomyopathy

“…The mitochondrial GTPase, OPA1 (optic atrophy 1), plays a major role in mitochondrial structure and function, regulating both the fusion of membranes and cristae ultrastructure 1 . OPA1 is associated with a wide range of pathologies in which mitochondrial dysfunction occurs, including neurodegenerative and cardiac diseases, as well as primary mitochondrial diseases such as dominant optic atrophy, Behr syndrome and Leigh‐like syndrome.…”

“…Mitochondrial dynamics are controlled by a set of dynamin‐related GTPase proteins, including fission proteins (Drp1 and its outer membrane receptors Fis1, Mff, MID49 and MID51), as well as fusion proteins (OPA1 and Mitofusins 1 and 2). OPA1 is located on both the inner mitochondrial membrane as well as the intermembrane space, depending on its processing, and induces fusion in concert with the outer GTPases, Mitofusins 1 and 2 1 . Mitochondrial dysfunction is a pathological hallmark of diabetic cardiomyopathy characterized by lower capacity for oxidative phosphorylation (OXPHOS), oxidative stress and abrogated mitochondrial quality control, 3 although the role of OPA1 in this setting is relatively unexplored.…”

“…Reduced SR‐mitochondria physical interaction can lower mitochondrial calcium uptake leading to lowered activation of Krebs cycle dehydrogenases, impaired ATP production and increased ROS production. Mitofusin 2 participates in this by tethering the SR to mitochondria 1 . Thus, its deficiency can contribute to impaired bioenergetics in the heart and the progressive loss of contractile function in heart failure.…”

“…In line with this, sirtuin 3, a main mitochondrial deacetylase, is important in facilitating high rates of myocardial fatty acid oxidation. OPA1 is controlled by various post‐translational mechanisms including acetylation, which could be responsible for OPA1‐mediated cristae remodelling 1 . Thus, the potential link between sirtuin 3 deficiency and impaired OPA1 activity, resulting in loss of cristae alignment and density, as well as lower mitochondrial ATP content, suggests that this may also occur in fatty acid metabolism disorders, such as diabetes, and is one of the underlying causes of mitochondrial dysfunction.…”

“…Furthermore, there may be other systemic effects in the diabetic animals treated with M1 that contribute to the observed improvements in diabetic cardiomyopathy, since plasma cholesterol was lower in the 12‐week diabetic animals that received M1 treatment. Beyond OPA1 protein levels, OPA1 activity is regulated through proteolytic cleavage of its different splice variants, as well as through its oligomerization 1,9 . OPA1 proteolytic processing regulates the balance of its long membrane‐bound forms and its short soluble forms, while its oligomerization regulates cristae ultrastructure during cell death and in response to energetic challenges.…”