MitoNEET, a key regulator of mitochondrial function and lipid homeostasis

Over the past decade, efforts have focused on the connection between mitochondrial dysfunction and the etiology of obesity, insulin resistance and the progression of type 2 diabetes mellitus (T2DM)1,2. Numerous studies indicate that metabolic disorders are accompanied with reduced mitochondrial content, compromised mitochondrial respiratory capacity, heightened oxidative-stress and consequently, altered whole-body lipid- and glucose metabolism3,4. The mechanisms that prompt compromised mitochondrial activity in obesity-driven T2DM and how targeting these processes will improve metabolic profiles remain largely unknown. Novel preclinical models that elucidate a role of mitochondria in cellular homeostasis have the potential to shed new light on these questions and allow us to define improved therapeutic avenues. Healthy adipose tissue (AT) expansion has potent anti-diabetic effects by providing a safe haven to neutralize and store excess free fatty acids (FFAs). The inability to appropriately expand subcutaneous white adipose tissue (sWAT) may underlie the development of insulin resistance, β-cell failure and T2DM5, by allowing the accumulation of lipid species that promote insulin resistance in cell-types vulnerable to lipotoxic effects. Adipocytes can also secrete adipokines that help buffer these lipotoxic side-effects of excess caloric-intake. A critical player in this area is adiponectin. Secreted exclusively from adipocytes, adiponectin promotes storage of triglycerides (TGs) preferentially in AT5,6 to improve metabolic flexibility. Adiponectin further reduces the accumulation of ceramide species to improve cellular survival and insulin sensitivity. Mice overexpressing adiponectin in an ob/ob background exhibit improved insulin-sensitivity and lipid profiles5; such characteristics are attributed to augmented ceramidase activity7, a redistribution of lipids and increased adipogenesis, concomitant with gross sWAT expansion. However, the underlying mechanisms that initiate this paradoxical phenomenon of lipid-redistribution and chronic AT expansion, to improve metabolic stature, are not fully defined. Mitochondria play a central role in energy homeostasis by partitioning fuels toward β-oxidation or storage as fat. During AT expansion, the oxidation of lipid and carbohydrate fuels requires coordinated regulation of downstream metabolic pathways, such as the tricarboxylic acid cycle and the electron transport chain (ETC). Compromised mitochondrial energy production is a major anomaly in obesity. In particular, obese and type 2 diabetic subjects are known to exhibit lower β-oxidation rates, reduced oxidative enzymatic activities and decreased ETC activity8,9; concomitant with greater glycolytic capacities and increases in cellular fatty acid (FA)-uptake10. While these observations highlight oxidative failure during lipid accumulation, the mechanisms by which diminished β-oxidation and suboptimal mitochondrial function stimulate lipid-uptake and accumulation within obesity, have not been fully established. Here, we take advantage of the unique properties of the mitochondrial membrane protein mitoNEET. Using gain and loss of function models for mitoNEET, we induce chronic and massive AT expansion, at least in part through an upregulation of adiponectin production and release from adipocytes. MitoNEET achieves these effects through a selective modulation of the mitochondrial electron transport activity. This establishes a tight functional connection between mitoNEET, mitochondrial activity and adiponectin release. Originally, mitoNEET was identified as a unique dimeric mitochondrial membrane target crosslinked to the thiazolidinedione (TZD), pioglitazone11,12. Located in the outer mitochondrial membrane, mitoNEET was named according to its C-terminal amino acid sequence, Asn-Glu-Glu-Thr (NEET)11. Furthermore, oriented towards the cytoplasm, the CDGSH domain of mitoNEET can bind redox-active, pH-labile 2Fe-2S clusters13–15; with pioglitazone reported to stabilize the protein against 2Fe-2S cluster release12. MitoNEET achieves its remarkable effects on cellular and systemic metabolic homeostasis on the basis of acting as a powerful regulator of mitochondrial iron content. We have taken advantage of these properties to influence mitochondrial bioenergetics and metabolism in a tissue- and cell-type specific manner; this results in remarkable alterations in whole-body energy homeostasis and further, opens up new avenues for cell-specific manipulation of mitochondrial activity in any cell-type of choice.