Wheel and Deal in the Mitochondrial Inner Membranes: The Tale of Cytochromecand Cardiolipin

Abstract

Cardiolipin oxidation and degradation by different factors under severe cell stress serve as a trigger for genetically encoded cell death programs. In this context, the interplay between cardiolipin and another mitochondrial factor—cytochrome c—is a key process in the early stages of apoptosis, and it is a matter of intense research. Cytochrome c interacts with lipid membranes by electrostatic interactions, hydrogen bonds, and hydrophobic effects. Experimental conditions (including pH, lipid composition, and post-translational modifications) determine which specific amino acid residues are involved in the interaction and influence the heme iron coordination state. In fact, up to four binding sites (A, C, N, and L), driven by different interactions, have been reported. Nevertheless, key aspects of the mechanism for cardiolipin oxidation by the hemeprotein are well established. First, cytochrome c acts as a pseudoperoxidase, a process orchestrated by tyrosine residues which are crucial for peroxygenase activity and sensitivity towards oxidation caused by protein self-degradation. Second, flexibility of two weakest folding units of the hemeprotein correlates with its peroxidase activity and the stability of the iron coordination sphere. Third, the diversity of the mode of interaction parallels a broad diversity in the specific reaction pathway. Thus, current knowledge has already enabled the design of novel drugs designed to successfully inhibit cardiolipin oxidation.

Met80 and Tyr67 affect the chemical unfolding of yeast cytochromec: comparing the solutionvs.immobilized state

“…[1][2][3][4][5][6][7] The solution properties and binding events affect the heme environment and axial ligation, 1,[3][4][5][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] modifying the physiological role in vivo and the reactivity in vitro. 1,5,9,[13][14][15][16]18,19,[28][29][30][31][32][33][34][35][36][37][38][39]…”

“…1,5,9,[13][14][15][16]18,19,[28][29][30][31][32][33][34][35][36][37][38][39][40] Indeed, cytochrome c has proven to be a multi-tasking protein whose biological role is modulated by external stimuli and cell conditions. 1,4,28,30,41 The paradigm of this tunable functionality in vivo is the interaction with cardiolipin (CL), a negatively charged glycerophospholipid found in the inner mitochondrial membrane (IMM), 30,40,42 which induces the cleavage of the Fe-S(Met80) bond, 1,5,9,19,21,28,30,32,39, imparting to cytc significant (lipo)peroxidase activity, which is crucial in triggering the apoptosis cascade. 1,5,28,30,40,47,73 In vitro, analogous heme axial ligand swapping from His/Met to His/His occurs upon chemical denaturation of both solution…”

“…1,4,28,30,41 The paradigm of this tunable functionality in vivo is the interaction with cardiolipin (CL), a negatively charged glycerophospholipid found in the inner mitochondrial membrane (IMM), 30,40,42 which induces the cleavage of the Fe-S(Met80) bond, 1,5,9,19,21,28,30,32,39, imparting to cytc significant (lipo)peroxidase activity, which is crucial in triggering the apoptosis cascade. 1,5,28,30,40,47,73 In vitro, analogous heme axial ligand swapping from His/Met to His/His occurs upon chemical denaturation of both solution 14 and surface-immobilized yeast cytochrome c (ycc). 14,33,34,[74][75][76][77] Under the latter conditions, ycc gains remarkable pseudo-peroxidase activity.…”

Exploring protein phosphorylation by combining computational approaches and biochemical methods

“…Further experimental NMR relaxation measurements and hydrogen–deuterium exchange experiments on the Y48 p CMF variant revealed that the structure of the ncAA mutant exhibits enhanced dynamics around the p CMF-containing loop (also observed in MD simulations), which could explain the changes observed in its functionality ( Table 4 ). Upon cardiolipin binding, C c undergoes conformational changes which allows H 2 O 2 to access the heme crevice [157] . In the absence of cardiolipin, Y48 p CMF C c displayed higher peroxidase activity compared to the Y48E phosphomimetic variant.…”

Megadalton-sized dityrosine aggregates of α-synuclein retain high degrees of structural disorder and internal dynamics

“…Cytochrome c (cyt c) resides in the inner mitochondrial membrane (IMM) where it is bound to cardiolipin, an organelle-specific, negatively-charged phospholipid (20). Under physiological cell conditions, cyt c transfers electrons between complex III and IV of the electron transport chain and oxidizes superoxide anions to molecular oxygen (O2) as a ROS scavenger.…”