Structure and Organization of Mitochondrial Cristae Membranes

Abstract

A fundamental question in biology, under investigation for over six decades, is the structural organization of mitochondrial cristae (singular = crista) membranes. Long known to harbor electron transport chain proteins (ETC), crista membrane integrity is key to establishment of the proton gradient that drives oxidative phosphorylation. Visualization of cristae morphology by electron microscopy/high voltage electron tomography has provided evidence that cristae are tube‐like extensions of the mitochondrial inner membrane (IM) that project into the matrix space. The signature lipid component of mitochondria, cardiolipin, comprises 18% of IM phospholipid mass. Unlike other glycerophospholipids, cardiolipin possesses two phosphatidyl moieties that share a glycerol head group. This combination of compact anionic polar head group and four esterified fatty acyl chains results in a distinctly cone‐shaped molecule. Based on its properties, cardiolipin has been classified as a “non‐bilayer” phospholipid. Interestingly, phosphatidylethanolamine (PE), which comprises 34% of IM phospholipid mass, is also a cone‐shaped, non‐bilayer phospholipid. How does a membrane that contains ~50% non‐bilayer phospholipids maintain a bilayer structure? Whereas a planar bilayer would not be able accommodate such high percentages of PE and cardiolipin, these phospholipids are well suited to reside in, and stabilize, a curved membrane. Taken together, ultrastructural and lipid compositional data provides support for a model of cristae as continuously curved cylinder‐shaped bilayer membranes capped by a dome‐shaped membrane tip. In this model of crista membrane structure cardiolipin and PE partition into the negatively curved monolayer leaflet facing the crista lumen while the opposing, positively curved, matrix facing monolayer leaflet contains predominantly phosphatidylcholine (~80%), with lesser amounts of phosphatidylinositol and phosphatidylserine. In addition to housing ETC proteins, cristae are home to the dynamin‐like GTPase, Opa1, the transacylase, tafazzin, the scaffold protein, prohibitin and the molecular chaperone, DNAJC19. These proteins function in distinctive ways to establish and maintain crista membrane lipid (i.e. cardiolipin) composition and structure. The accumulation of negative curvature lipids along with the presence of protein factors that establish and maintain crista structure, have a direct impact on mitochondrial functions including oxidative phosphorylation, fusion/fission and apoptosis.Support or Funding InformationNIH R37 HL64159NIH T32 DK061918