At the pyruvate branch point, the fermentative and oxidative metabolic routes diverge. Pyruvate can be transformed either into lactate in mammalian cells or into ethanol in yeast, or transported into mitochondria to fuel ATP production by oxidative phosphorylation. The recently discovered mitochondrial pyruvate carrier (MPC), encoded by MPC1, MPC2, and MPC3 in yeast, is required for uptake of pyruvate into the organelle. Here, we show that while expression of Mpc1 is not dependent on the carbon source, expression of Mpc2 and Mpc3 is specific to fermentative or respiratory conditions, respectively. This gives rise to two alternative carrier complexes that we have termed MPCFERM and MPCOX. By constitutively expressing the two alternative complexes in yeast deleted for all three endogenous genes, we show that MPCOX has a higher transport activity than MPCFERM, which is dependent on the C‐terminus of Mpc3. We propose that the alternative MPC subunit expression in yeast provides a way of adapting cellular metabolism to the nutrient availability.

Protein aggregation negatively affects key enzymes of major metabolic pathways in mitochondria. The main mitochondrial chaperones Hsp70 and Hsp60 have a limited protective effect against aggregation. In contrast, the ATP-dependent matrix protease Pim1/LON significantly reduces aggregate levels by preventing the accumulation of damaged polypeptides.

Mitochondria play a key role in energy metabolism, hosting the machinery for oxidative phosphorylation, the most efficient cellular pathway for generating ATP. A major checkpoint in this process is the transport of pyruvate produced by cytosolic glycolysis into the mitochondrial matrix, which is accomplished by the recently identified mitochondrial pyruvate carrier (MPC). As the gatekeeper for pyruvate entry into mitochondria, the MPC is thought to be of fundamental importance in establishing the metabolic programming of a cell. This is especially relevant in the context of the aerobic glycolysis, also known as the Warburg effect, which is a hallmark in many types of cancer, and MPC loss of function promotes cancer growth. Moreover, mitochondrial pyruvate uptake is needed for efficient hepatic gluconeogenesis and the regulation of blood glucose levels. In this review we discuss recent advances in our knowledge of the MPC, and we argue that it may offer a promising target in diseases like cancer and type 2 diabetes. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Mitochondria contribute significantly to the cellular production of ROS. The deleterious effects of increased ROS levels have been implicated in a wide variety of pathological reactions. Apart from a direct detoxification of ROS molecules, protein quality control mechanisms are thought to protect protein functions in the presence of elevated ROS levels. The reactivities of molecular chaperones and proteases remove damaged polypeptides, maintaining enzyme activities, thereby contributing to cellular survival both under normal and stress conditions. We characterized the impact of oxidative stress on mitochondrial protein homeostasis by performing a proteomic analysis of isolated yeast mitochondria, determining the changes in protein abundance after ROS treatments. We identified a set of mitochondrial proteins as substrates of ROS-dependent proteolysis. Enzymes containing oxidation-sensitive prosthetic groups like iron/sulfur clusters represented major targets of stress-dependent degradation. We found that several proteins involved in ROS detoxification were also affected. We identified the ATP-dependent protease Pim1/LON as a major factor in the degradation of ROS-modified soluble polypeptides localized in the matrix compartment. As Pim1/LON expression was induced significantly under ROS treatment, we propose that this protease system performs a crucial protective function under oxidative stress conditions.