Summary: PGC1α is a transcriptional coactivator that is a central inducer of mitochondrial biogenesis in cells. Recent work highlighted that PGC1α can also modulate the composition and functions of individual mitochondria. Therefore, it is emerging that PGC1α is controlling global oxidative metabolism by performing two types of remodelling: (1) cellular remodelling through mitochondrial biogenesis, and (2) organelle remodelling through alteration in the intrinsic properties of mitochondria. The elevated oxidative metabolism associated with increased PGC1α activity could be accompanied by an increase in reactive oxygen species (ROS) that are primarily generated by mitochondria. However, increasing evidence suggests that this is not the case, as PGC1α is also a powerful regulator of ROS removal by increasing the expression of numerous ROS-detoxifying enzymes. Therefore, PGC1α, by controlling both the induction of mitochondrial metabolism and the removal of its ROS by-products, would elevate oxidative metabolism and minimize the impact of ROS on cell physiology. In this Commentary, we discuss how the biogenesis and remodelling of mitochondria that are elicited by PGC1α contribute to an increase in oxidative metabolism and the preservation of ROS homeostasis. Finally, we examine the importance of these findings in ageing and neurodegenerative disorders, conditions that are associated with impaired mitochondrial functions and ROS balance.

Ca²⁺ transport across the inner membrane of mitochondria (IMM) is of major importance for their functions in bioenergetics, cell death and signaling. It is therefore tightly regulated. It has been recently proposed that LETM1—an IMM protein with a crucial role in mitochondrial K⁺/H⁺ exchange and volume homeostasis—also acts as a Ca²⁺/H⁺ exchanger. Here we show for the first time that lowering LETM1 gene expression by shRNA hampers mitochondrial K⁺/H⁺ and Na⁺/H⁺ exchange. Decreased exchange activity resulted in matrix K⁺ accumulation in these mitochondria. Furthermore, LETM1 depletion selectively decreased Na⁺/Ca²⁺ exchange mediated by NCLX, as observed in the presence of ruthenium red, a blocker of the Mitochondrial Ca²⁺ Uniporter (MCU). These data confirm a key role of LETM1 in monovalent cation homeostasis, and suggest that the effects of its modulation on mitochondrial transmembrane Ca²⁺ fluxes may reflect those on Na⁺/H⁺ exchange activity.

Mitochondrial Ca ²⁺ ions are crucial regulators of bioenergetics and cell death pathways. Mitochondrial Ca ²⁺ content and cytosolic Ca ²⁺ homeostasis strictly depend on Ca ²⁺ transporters. In recent decades, the major players responsible for mitochondrial Ca ²⁺ uptake and release have been identified, except the mitochondrial Ca ²⁺ /H ⁺ exchanger (CHE). Originally identified as the mitochondrial K ⁺ /H ⁺ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identify TMBIM5/MICS1, the only mitochondrial member of the TMBIM family, and validate the physical interaction of TMBIM5 and LETM1. Cell‐based and cell‐free biochemical assays demonstrate the absence or greatly reduced Na ⁺ ‐independent mitochondrial Ca ²⁺ release in TMBIM5 knockout or pH‐sensing site mutants, respectively, and pH‐dependent Ca ²⁺ transport by recombinant TMBIM5. Taken together, we demonstrate that TMBIM5, but not LETM1, is the long‐sought mitochondrial CHE, involved in setting and regulating the mitochondrial proton gradient. This finding provides the final piece of the puzzle of mitochondrial Ca ²⁺ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca ²⁺ exchange.

Mitochondrial function is essential for life. Therefore, it is unsurprising that perturbations in mitochondrial function have wide-ranging consequences in the cell. High-throughput screening has identified essential genes required for cellular survival and fitness. One such gene is LETM1. The undisputed function of LETM1 from yeast to human is to maintain the mitochondrial osmotic balance. Osmotic imbalance has been demonstrated to affect mitochondrial morphology, dynamics, and, more recently, metabolism. Whether conservation of osmotic homeostasis by LETM1 occurs by extrusion of excess mitochondrial potassium (K⁺), calcium (Ca²⁺), or both has been a matter of dispute over the past 10 years. In this Opinion, we report and discuss recent findings on LETM1 structure, essentiality, and function and its involvement in Wolf-Hirschhorn syndrome (WHS) and seizures.

Epidemiologic and experimental data have led to increased interest in possible roles of biguanides in cancer prevention and/or treatment. Prior studies suggest that the primary action of metformin is inhibition of oxidative phosphorylation, resulting in reduced mitochondrial ATP production and activation of AMPK. In vitro, this may lead to AMPK-dependent growth inhibition if AMPK and its effector pathways are intact or to an energetic crisis if these are defective. We now show that the effect of exposure of several transformed cell lines to metformin varies with carbon source: in the presence of glutamine and absence of glucose, a 75% decrease in cellular ATP and an 80% decrease in cell number is typical; in contrast, when glucose is present, metformin exposure leads to increased glycolysis, with only a modest reduction in ATP level and cell number. Overexpression of myc was associated with sensitization to the antiproliferative effects of metformin, consistent with myc involvement in “glutamine addiction”. Our results reveal previously unrecognized factors that influence metformin sensitivity and suggest that metformin-induced increase in glycolysis attenuates the antiproliferative effects of the compound. Cancer Res; 72(23); 6257–67. ©2012 AACR.