What comes first, misshape or dysfunction? The view from metabolic excess

In typical cultured animal cells, mitochondria exist in shapes ranging from long interconnected tubules, often clustered in the perinuclear region of the cell, to small spherical forms in the cell periphery. However, mitochondrial appearance at any given moment in time is only a snapshot of dynamic change of morphology, which may or may not be the same in future observations dependent on the stimuli/stresses encountered. Fission and fusion are the main processes for changing mitochondrial morphology, governed by dynamin-related large GTPases: DLP1/Drp1 for fission, and Mfn1/2 and OPA1 for fusion of the outer mitochondrial membrane and inner membrane, respectively. The requirement for energy in these processes along with their requisite roles in cell life and death through mitophagy and apoptosis emphasizes the critical function of mitochondrial fission and fusion. Indeed, pathological conditions such as the hereditary neuropathies Charcot–Marie–Tooth type 2A and optic atrophy type 1 arise from mutations in Mfn2 and OPA1, respectively (Alexander et al., 2000; Delettre et al., 2000; Züchner et al., 2004). Metabolic disease pathologies are also associated with progressive mitochondrial dysfunction and alterations in mitochondrial morphology. These pathologies include but are not limited to diabetic tissue damage, such as diabetic cardiomyopathy (DCM) and the commonly associated hepatic pathology of nonalcoholic fatty liver disease (NAFLD). This article discusses the current knowledge connecting mitochondrial form and function in relation to metabolic disease, highlighting a plausible mechanistic linkage of mitochondrial morphology and metabolic disease.