Nutrient availability links mitochondria, apoptosis, and obesity

Abstract

Mitochondria are the dominant source of the cellular energy requirements through oxidative phosphorylation, but they are also central players in apoptosis. Nutrient availability may have been the main evolutionary driving force behind these opposite mitochondrial functions: production of energy to sustain life and release of apoptotic proteins to trigger cell death. Here, we explore the link between nutrients, mitochondria and apoptosis with known and potential implications for age-related decline and metabolic syndromes.

Figure 1. Mitochondrial structure

Mitochondrial membranes delimit the IMS and the matrix. This last compartment hosts the mitochondrial metabolic pathways, such as TAC cycle, β-oxidation and heme synthesis. MIM contains ETC complexes and ATP synthase. Complex I, III and IV extrude protons from the matrix in the IMS creating a proton gradient or mitochondrial membrane potential. The retrograde flux of ions promoted by complex V (ATP Synthase) liberates the energy necessary to phosphorylate ADP to ATP; upper inset. Fundamental for mitochondrial homeostasis and function are several exchange carries, such as the malate-aspartate shuttle in which cytosolic oxaloacetate is reduced to malate in a NADH-dependent reaction and malate is then imported in the mitochondrial matrix and oxidized back to oxaloacetate by malate dehydrogenase with the conversion of NAD+ to NADH; lower inset. α-KG, α-ketoglutarate; OAA, Oxaloacetate; Glu, Glutamate, cyt-c, cytochrome c.

Figure 2. Mitochondrial apoptosis links nutritional status with metabolic syndromes

Caloric restriction leads to an improvement of the mitochondrial function stimulating mitochondrial biogenesis and fusion, and increasing ETC efficiency with a decreased production of ROS. High caloric intake decreases levels of PCG-1α and Mfn2 leading to reduced mitochondrial fusion and compromising organelle functions. Moreover, in obesity apoptotic pathways proteins are upregulated and increased apoptosis has been reported in adipocytes. This cell death is strongly dependent on mitochondria as the extrinsic pathway can also activate the intrinsic pathway by caspase-8 mediated cleavage of the BH3-only protein Bid, resulting in the formation of the active truncated isoform tBid. Genetic depletion of Bid protects against obesity-induced metabolic syndrome. Other cell lines, such stem cells, might suffer a similar mitochondrial dysfunction during obesity and become more sensitive to apoptosis, which in turn, will worsen age and age-related metabolic syndromes.