Cellular and molecular mechanisms of mitochondrial function

Abstract

Mitochondria are membrane bound organelles present in almost all eukaryotic cells. Responsible for orchestrating cellular energy production, they are central to the maintenance of life and the gatekeepers of cell death. Thought to have originated from symbiotic ancestors, they carry a residual genome as mtDNA encoding 13 proteins essential for respiratory chain function. Mitochondria comprise an inner and outer membrane that separate and maintain the aqueous regions, the intermembrane space and the matrix. Mitochondria contribute to many processes central to cellular function and dysfunction including calcium signalling, cell growth and differentiation, cell cycle control and cell death. Mitochondrial shape and positioning in cells is crucial and is tightly regulated by processes of fission and fusion, biogenesis and autophagy, ensuring a relatively constant mitochondrial population. Mitochondrial dysfunction is implicated in metabolic and age related disorders, neurodegenerative diseases and ischemic injury in heart and brain.

Fig. 1

Bioenergetics of the electron transport chain and the TCA/Kerbs cycle. Pyruvate is converted to high-energy molecules LIKE NADH, GTP and FADH₂ through catalyzation by TCA/Kerbs cycle enzymes. NADH generated is shuttled to complex I and is converted to NAD⁺ driving oxidative phosphorylation. Transfer of electrons through the chain maintains the membrane potential via proton pumping into the IMS. In this final step ADP is phosphorylated to form ATP via complex V (ATP synthase).

Fig. 2

Mitochondrial dynamics. Steady state mitochondrial morphology requires a balance of fission and fusion events. Organelle division is mediated by Drp1 which forms high molecular weight oligomers on the mitochondrial surface. Once Drp1 is released fission is complete. Mitochondrial fusion is a two-step process that requires outer and inner membrane fusion. Outer membrane fusion is facilitated by mitofusin tethering of adjacent membranes. In high GTP environments, OPA1 isoforms allow inner membrane fusion.

Fig. 3

Apoptotic activation via the intrinstic pathway. Apoptotic stimuli activates the BH3-only proteins, concurrently inactivating Bcl-2 and activating Bax translocation to mitochondria. Bak is held in check by Mcl-1, VDAC2 and Bcl-xL. Bax/Bakoligomerisation results in cytochrome c release and MOMP. apaf-1 is activated by cytochrome c binding, displacing the CARD domain. The apoptosome forms with caspase-9, activating caspase-3 and triggering apoptosis.