Regulation and functional role of the electron transport chain supercomplexes

Abstract

Mitochondria are one of the most exhaustively investigated organelles in the cell and most attention has been paid to the components of the mitochondrial electron transport chain (ETC) in the last 100 years. The ETC collects electrons from NADH or FADH2 and transfers them through a series of electron carriers within multiprotein respiratory complexes (complex I to IV) to oxygen, therefore generating an electrochemical gradient that can be used by the F1-F0-ATP synthase (also named complex V) in the mitochondrial inner membrane to synthesize ATP. The organization and function of the ETC is a continuous source of surprises. One of the latest is the discovery that the respiratory complexes can assemble to form a variety of larger structures called super-complexes (SCs). This opened an unexpected level of complexity in this well-known and fundamental biological process. This review will focus on the current evidence for the formation of different SCs and will explore how they modulate the ETC organization according to the metabolic state. Since the field is rapidly growing, we also comment on the experimental techniques used to describe these SC and hope that this overview may inspire new technologies that will help to advance the field.

Keywords: N-respirasome; OXPHOS; Q-respirsome; electon transport chain; supercomplexes.

Figure 1.. Mitochondrial ETC is the central hub of cellular bioenergetics.

Anabolic (amino acid metabolism and nucleotide biosynthesis) and catabolic reactions (glycolysis, TCA cycle, β-oxidation and amino acid oxidation) release electrons stored as FADH or NADH to the ETC that channel them to CoQ. In the picture is outlined the electron flux from the different enzymes of metabolic pathways to the complexes and super-complexes of the ETC. FADH₂ dependent enzymes attached to it, while NADH generated by a variety of metabolic process navigate to respiratory CI to be oxidized. Anabolic pathways are shown in green and catabolic pathways in red. The following pdb structures were used to develop this figure: 6idj (DHODH, Homo sapiens), 5m42 (proDH, Thermus thermophilus), 6iq6 (G3PDH, Homo sapiens), 6oi5 (SQOR, Homo sapiens), 2gmh (ETFDH, Sus scrofa), CI (5xtd, Homo sapiens), CII (4ytp, Sus scrofa), CIII2 (5xte, Homo sapiens), CIV (5z62, Homo sapiens), CIV2 (1occ, Bos taurus), ATPase (6tt7, Ovis aries), Tight N-respirosome (5j4z, Ovis aries) and lipidic bilayer (2mlr).

Figure 2.. Respiratory complexes and SCs composition.

(a) Respiratory super-complexes are formed by different composition of complexes. Key factors are the expression of different subunit isoforms important for CIV dimerization (COX7A2, COX7A1, COX6A1, COX6A2), the assembly factors SCAF1 (important for CIII and IV interaction) and MCJ (inhibitor of CI and CIII assembly), MIM lipid composition (CL: cardiolipin, PE: phosphatidylethanolamine, PG: plasmalogen). (b) Respirasome alternative ternary interactions. N-respirasome may include a single copy of CIV2 instead of CIV. Moreover, the stoichiometry of megacomplex (2I + III₂ + 2IV) is represented. The following pdb structures were used to develop this figure: CI (5xtd, Homo sapiens), CIII2 (5xte, Homo sapiens), CIV (5z62, Homo sapiens), CIV2 (1occ, Bos taurus), Loose N-respirasome (5j7y, Ovis aries), Tight N-respirasome (5j4z, Ovis aries) and Megacomplex (Homo sapiens, Bos taurus). c) BN-PAGE of 2 h [³⁵S]-methionine pulse labeled mtDNA encoded proteins wild-type mouse embryonic fibroblasts from and harvested after 24 h of chase.

Figure 3.. Metabolic adaptation of super-complexes.

Super-complexes formation undergoes to adaptation upon different metabolic conditions. During development, the formation of super-complexes follows a genetically coordinated timing. Exercise improves super-complexes formation probably trough a ROS/UPR/PERK mediated pathway. Endoplasmic reticulum stress response triggers SCs assembly through the PERK axis that activates both SCAF1 expression and cristae formation. The accumulative damage may be due to ROS increasing is responsible of super-complexes damage during aging and probably also in diabetes mellitus (DM) and heart failure. The massive dependency on anabolic reactions of cancer cells could be responsible of the super-complexes increase. Diet and in particular the ratio NADH/FADH₂ modulate super-complexes distribution through RET. The different expression levels of SCAF1 in different tissues could be responsible of the variability in CIII₂ + IV and CI + III₂ + IV amount. Expression data obtained from Human Protein Atlas available from http://www.proteinatlas.org. The following pdb structures were used to develop this figure: CI (5xtd, Homo sapiens), CIII2 (5xte, Homo sapiens) and CIV (5z62, Homo sapiens).