Calcium flux

The mitochondrial calcium (Ca²⁺) uniporter complexes (MCUs) and MAMs are 2 structures that control Ca²⁺flux and therefore play roles in obesity-associated changes in bioenergetics. These complexes coordinate with signaling pathways downstream of surface receptors like the T-cell receptor to activate protein kinase C (Fig. 1D). MCU supports the store-operated calcium entry response following release of Ca²⁺from the endoplasmic reticulum to control multiple inflammatory mediators including the inflammasome, Th17 differentiation, and NF-κB activation (60-62). Ca²⁺also moves into the mitochondria through MAMs, which coordinate essential crosstalk between mitochondria and the endoplasmic reticulum. MAMs are involved in a myriad of inflammatory and cellular regulation mechanisms (eg, inflammasome activation and ROS production), among others (63). Individuals with obesity have more MAM area, likely because obesity causes an increase in the steady-state levels of MAM proteins (64). This increase in MAM formation in obesity has been established as a significant factor in harmful metabolic changes. MAMs also contribute to glucose homeostasis and hepatic insulin resistance, and thus to the development of T2D (65, 66). Although the mechanistic details of MAM alteration during obesity remain in development (64), the intra-MAM distance between the mitochondria and the endoplasmic reticulum increases following chronic high glucose, with protein complexes such as inositol 1,4,5-triphosphate receptors and mitochondria-shaping mitofusins contributing to interorganelle distance and Ca^2 +transport. MAM dysregulation in obesity and T2D not only affects Ca²⁺signaling, but also impacts insulin signaling: some critical signaling proteins for insulin usage are located in the MAM interface or are in close physical approximation with MAMs (64, 67-69). MAMs are important for rapid reprogramming and effector functions of memory CD8⁺T cells through activation-induced engagement of the mTORC2-protein kinase B-glycogen synthase kinase 3β pathway, which was critical for recruitment of hexokinase 1 to the mitochondria via VDAC and downstream IFNγ production. These pathways have not been investigated in CD4⁺T cells, nor the context of obesity (70). Anti-obesity roles for MAMs have also been reported (reviewed in (67)).

In addition to the cross-talk among mitochondrial regulatory mechanisms outlined previously, the important concept of mitochondrial heterogeneity remains largely unexplored in obesity (reviewed in (71, 72)). This area of future work will be especially challenging for analysis of primary cells from people with obesity and/or T2D apart from mitochondrially rich tissues like muscle or neurons.