The human brain possesses three predominate phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), which account for approximately 35–40%, 35–40%, and 20% of the brain’s phospholipids, respectively. Mitochondrial membranes are relatively diverse, containing the aforementioned PC, PE, and PS, as well as phosphatidylinositol (PI) and phosphatidic acid (PA); however, cardiolipin (CL) and phosphatidylglycerol (PG) are exclusively present in mitochondrial membranes. These phospholipid interactions play an essential role in mitochondrial fusion and fission dynamics, leading to the maintenance of mitochondrial structural and signaling pathways. The essential nature of these phospholipids is demonstrated through the inability of mitochondria to tolerate alteration in these specific phospholipids, with changes leading to mitochondrial damage resulting in neural degeneration. This review will emphasize how the structure of phospholipids relates to their physiologic function, how their metabolism facilitates signaling, and the role of organ- and mitochondria-specific phospholipid compositions. Finally, we will discuss the effects of global ischemia and reperfusion on organ- and mitochondria-specific phospholipids alongside the novel therapeutics that may protect against injury.

Significance: Coenzyme B ₁₂ (or 5′-deoxyadenosylcobalamin [AdoCbl]) is a cofactor for methylmalonyl-CoA mutase (MCM), which is important for propionate metabolism in Mycobacterium tuberculosis and for anaplerosis in humans. AdoCbl is synthesized by adenosyltransferase (ATR), which doubles as an escort, delivering the cofactor to MCM. The mechanism by which this large cofactor is translocated from ATR to MCM is not known. Our crystal structures of M. tuberculosis ATR reveal that mobile loops dynamically create a customized pocket to control cofactor coordination and conformation, regulating its reactivity and transportability. These changes also control solvent exposure and signaling to MCM when ATR is ready to transfer cargo, in a process where the cofactor tail plays an important role in the handover between proteins.