TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy.

Ion fluxes across the inner mitochondrial membrane control mitochondrial volume, energy production, and apoptosis. TMBIM5, a highly conserved protein with homology to putative pH-dependent ion channels, is involved in the maintenance of mitochondrial cristae architecture, ATP production, and apoptosis. Here, we demonstrate that overexpressed TMBIM5 can mediate mitochondrial calcium uptake. Under steady-state conditions, loss of TMBIM5 results in increased potassium and reduced proton levels in the mitochondrial matrix caused by attenuated exchange of these ions. To identify the in vivo consequences of TMBIM5 dysfunction, we generated mice carrying a mutation in the channel pore. These mutant mice display increased embryonic or perinatal lethality and a skeletal myopathy which strongly correlates with tissue-specific disruption of cristae architecture, early opening of the mitochondrial permeability transition pore, reduced calcium uptake capability, and mitochondrial swelling. Our results demonstrate that TMBIM5 is an essential and important part of the mitochondrial ion transport system machinery with particular importance for embryonic development and muscle function.

Regular physical exercise mediates the immune response in atherosclerosis.

Atherosclerosis is a chronic inflammatory cardiovascular disease, which results from lipid accumulation in the blood vessel wall, forming a plaque, and ultimately restricting blood flow. The immune system plays a vital role in progression to plaque rupture. While recent evidence clearly indicates the anti-inflammatory function of regular exercise, the mechanisms by which regular exercise can modulate its pathophysiology is not well understood. In this review, we discuss how regular exercise can lower systemic inflammation directly via modulation of the immune system or indirectly via altered myokine concentrations and metabolites. We describe the exercise-induced responses of various myokines (such as IL-6, adiponectin, and FGF21), and how cell function in the innate immune system can be modulated via regular exercise, with the aim to modulate plaque formation in atherosclerosis.