Mitochondrial Calcium Uniporter Regulates Metabolic Remodeling and Smooth Muscle Cell Proliferation in Type 2 Diabetes

Abstract

Background: Excessive proliferation of vascular smooth muscle cells (VSMCs) is a consequence of type 2 diabetes (T2D) that increases the risk for atherosclerosis and restenosis after angioplasty. Here, we sought to determine whether and how mitochondrial dysfunction in T2D drives VSMC proliferation with a focus on increased reactive oxygen species and intracellular [Ca²⁺] that both drive cell proliferation, occur in T2D, and are regulated by the mitochondrial Ca²⁺ uniporter (MCU).

Methods: Using a mouse model of T2D, we performed in vivo phenotyping after mechanical injury and established the mechanisms of excessive proliferation in cultured VSMCs. The T2D model was induced by high-fat diet and low-dose streptozotocin in both wild type mice and mice with the VSMC-specific inhibition of the mtCaMKII (mitochondrial Ca²⁺/calmodulin-dependent kinase IImtCaMKII), a regulator of Ca²⁺ entry via the MCU.

Results: In VSMCs from T2D model mice, MCU inhibition reduced both in vivo neointima formation after mechanical injury, as well as in vitro proliferation of cultured VSMCs. Further, in VSMCs from T2D mice, the composition of the MCU complex and MCU activity were altered with loss of MICU1 (mitochondrial calcium uptake 1). In addition, VSMC mitochondrial reactive oxygen species was elevated and mitochondrial respiration blunted. The increase in cytosolic reactive oxygen species induced activation of G6PD (glucose-6-phosphate dehydrogenase), a key enzyme of the pentose phosphate pathway. However, inhibiting MCU or MICU1 overexpression on VSMCs from T2D mice decreased intracellular reactive oxygen species, preserved mitochondrial respiration and ATP production, decreased activity of G6PD, and normalized cell proliferation. These data suggest the MCU complex controls a T2D-induced metabolic switch that promotes cell proliferation.

Conclusions: Collectively, these data indicate that MCU complex remodeling in T2D drives neointimal restenosis, suggesting MCU as a therapeutic target.

Keywords: diabetes; metabolism; mitochondria; neointima; vascular smooth muscle cells.