Mitochondrial Structure and Bioenergetics in Normal and Disease Conditions

Abstract

Mitochondria are ubiquitous intracellular organelles found in almost all eukaryotes and involved in various aspects of cellular life, with a primary role in energy production. The interest in this organelle has grown stronger with the discovery of their link to various pathologies, including cancer, aging and neurodegenerative diseases. Indeed, dysfunctional mitochondria cannot provide the required energy to tissues with a high-energy demand, such as heart, brain and muscles, leading to a large spectrum of clinical phenotypes. Mitochondrial defects are at the origin of a group of clinically heterogeneous pathologies, called mitochondrial diseases, with an incidence of 1 in 5000 live births. Primary mitochondrial diseases are associated with genetic mutations both in nuclear and mitochondrial DNA (mtDNA), affecting genes involved in every aspect of the organelle function. As a consequence, it is difficult to find a common cause for mitochondrial diseases and, subsequently, to offer a precise clinical definition of the pathology. Moreover, the complexity of this condition makes it challenging to identify possible therapies or drug targets.

Keywords: ATP production; biogenesis of the respiratory chain; mi-tochondrial electrochemical gradient; mitochondrial disease; mitochondrial potential; mitochondrial proton pumping; mitochondrial respiratory chain; oxidative phosphorylation; respiratory complex; respiratory supercomplex.

Figure 1

Schematic representation of mitochondrial DNA (mtDNA). Each protein-encoding gene is indicated with a colored bar and all the genes encoding for subunits of the same complex are represented with the same color. rRNAs are indicated in yellow and tRNAs in gray. Source: adapted from Hoffmann and Spengler, 2018 [6].

Figure 11

Schematic representation of human CIII assembly model based on the homology with the available data for S. cerevisiae [217,218,219,221,232,233,236,250,254,257], and of our updated model [220].

Figure 12

Representation of bovine CIV dimeric structure, obtained from X-ray crystallography (SFX). The functional core of the complex is composed of the mitochondrial-encoded subunits MTCO1 (green), MTCO2 (dark blue) and MTCO3 (yellow). Source: adapted from Ishigami et al., 2017 [303].

Figure 14

Overall structure of porcine respirasome (I₁III₂IV₁). Source: adapted from Milenkovic et al., 2017 [452].

Figure 2

Schematic representation of mitochondrial architecture. The outer mitochondrial membrane (OMM), inner mitochondrial membrane (IMM), inner boundary membrane (IBM), cristae junctions (CJ), intermembrane space (IMS), cristae and mitochondrial matrix are indicated.

Figure 3

Cartoon of the mitochondrial contact site and cristae organizing system (MICOS) complex at the cristae junction. Source: adapted from Guarani et al., 2015 [17].

Figure 4

Schematic representation of the tricarboxylic acid cycle or Krebs cycle.

Figure 5

Cartoon representation of the oxidative phosphorylation (OXPHOS) machinery. NADH and FADH2 molecules generated during glycolysis and the Krebs cycle are oxidized by complex I (CI) and complex II (CII), respectively. Electrons are then passed to ubiquinone (Q), which transfers them to complex III (CIII). Here, they are transferred to cytochrome c (C) and to complex IV (CIV), where they are used to reduce O₂ to H₂O. Coupled to electron transfer, protons are pumped from the matrix (red arrows) to the intermembrane space (IMS) and the proton motive force generated is used by complex V (CV) to produce ATP.

Figure 6

Graphic representation of electrons flow through the electron transport chain (ETC) from NADH, succinate and FADH₂ to O₂ (dotted arrows). The catalytic centers of the four electron transport chain complexes are represented. Electrons pass in sequence from carriers with a lower reduction potential to those with a higher potential. The energy released from the passage of electrons through the chain is coupled with the pumping of protons across the inner membrane, establishing the proton motive force (PMF). Adapted from Molecular Cell Biology, 4th edition. W. H. Freeman, New York.

Figure 7

Schematic representation of the Q-cycle.

Figure 8

Representation of CI structure. Image has been created with BioRender.com using the structural data retrieved from PDB (5LC5).

Figure 9

Representation of E. coli CII structure. The four subunits forming the complex (SDHA-D) are shown in different colors and labeled with the letters A to D. FAD, Fe-S centers, heme b and the ubiquinone binding site facing the matrix (Qp) are indicated. Source: Iverson, 2013 [181].

Figure 10

Representation of bovine CIII structure. CIII is shown as a dimer, the only form in which it is found in cells. All the 10 subunits are represented with a different color in one monomer. Source: Sousa et al., 2018 [207].

Figure 13

Representation of S. cerevisiae CV structure. The main subunits of the enzyme are indicated and shown in different colors. Source: adapted from Kuhlbrandt, 2019 [394].