Table 1 |.
Mitochondrial functions and behaviours
| Description | Reviewed in ref(s). | Methods described in ref(s). | |||
|---|---|---|---|---|---|
| Functions | |||||
| a Membrane potential generation | Formation of the electrochemical gradient (ΔΨm+ΔpH) across the IMM, usually by the electron pumping capacity of the respiratory complexes I, III and IV, but also by other processes including through ATP hydrolysis by the FoF1 ATP synthase (complex V). | 104 | 105,106 | ||
| Amino acid metabolism | Lysine metabolism (lysine-α-ketoglutarate reductase, encoded by AASS). Electrogenic malate–aspartate shuttle system, which is important for balancing pyridine dinucleotide redox states across subcellular compartments. Branched-chain keto and amino acids. Choline and derivatives as structural precursors for lipoproteins, membrane lipids and the neurotransmitter acetylcholine. Betaine as osmoregulator and an intermediate in the cytosolic transulfuration pathway. | 107–111 | 112–119 | ||
| Ascorbate metabolism | l-ascorbate (vitamin C) biosynthesis in many plants and animals, but not in primates, which serves as osmoregulator and antioxidant. Mitochondria may recycle oxidized (dehydro)ascorbic acid. | 120 | 121,122 | ||
| Bicarbonate metabolism | Production of bicarbonate (HCO3−) by mitochondrial carbonic anhydrase V (encoded by CA5A), used as a cofactor for anaplerotic reactions (for example, ureagenesis and gluconeogenesis) and acid–base balance. The TCA cycle is an important contributor to cellular/extracellular acidification due to CO2 production. | 123 | – | ||
| Calcium uptake and extrusion | Uptake of cytoplasmic Ca2+ via the mitochondrial calcium uniporter in a ΔΨm-dependent manner; extrusion by the sodium/calcium exchanger NCLX (encoded by SLC8B1). | 124–126 | 127,128 | ||
| Hydrogen sulfide detoxification | Mitochondrial sulfide quinone oxidoreductase (encoded by SQOR) oxidizes hydrogen sulfide to glutathione persulfide by reducing CoQ. | 129–132 | 133 | ||
| Heat production | Heat generation is stimulated by uncoupling ΔΨm+ΔpH from ATP synthesis (thereby increasing electron flux and respiration) by UCP1 (encoded by UCP1), the ADP/ATP carrier (AAC, also ANT1), or by creatine-dependent substrate cycling and other futile cycles. | 134–137 | 138 | ||
| Intermediate metabolism | Enzymatic interconversion of metabolic intermediates to enable the synthesis of specific macromolecules, including five major anaplerotic ones. This includes the conversion of pyruvate into oxaloacetate by pyruvate carboxylase (encoded by PC), a critical step for de novo glucose synthesis (gluconeogenesis); citrate export to the cytoplasm where it is used for lipid synthesis or converted to acetyl-CoA for acetylation reactions; synthesis of itaconate, a derivative of cis-aconitate; succinate, α-ketoglutarate and others that participate in a variety of signalling process. | 25,139,140 | 141,142 | ||
| Fe/S cluster synthesis | Synthesis of Fe/S clusters, which serve as prosthetic groups of several essential proteins. | 12–14 | 143 | ||
| Light focusing | Mitochondria in the outer segment of the retinal photoreceptors acts as a ‘microlens’ that focuses incoming photons, increasing visual resolution. | 144 | – | ||
| Lipid oxidation | Beta-oxidation of long-chain, medium-chain and short-chain fatty acids into acetyl-CoA. | 145 | 146 | ||
| Lipid synthesis | Synthesis of cardiolipin and phosphatidylethanolamine from ER precursors in the IMM. | 147–150 | – | ||
| mtDNA maintenance and expression | mtDNA replication, transcription, protein synthesis and assembly of the OxPhos system. | 151,152 | 153,154 | ||
| Na+import/export | Sodium (Na+) uptake and release against cytoplasmic Ca2+ by the sodium/calcium exchanger protein NCLX (encoded by SLC8B1) or by Na+/H+ antiporter (molecular identity pending). | 124,155 | 156 | ||
| Neurotransmitter synthesis and degradation | Synthesis of the cofactor BH4 (tetrahydrobiopterin), used by hydrolase enzymes to synthesize catecholamines and neurotransmitters (serotonin, melatonin, norepinephrine and epinephrine) and nitric oxide. Mitochondria with OMM-anchored monoamine oxidases (encoded by MAOA and MAOB, donate electrons and contribute to electron flow in the ETC) also degrade catecholamines. Mitochondria also participate in GABA metabolism. | 9,157 | 158,159 | ||
| One-carbon metabolism and pyrimidine synthesis | The one-carbon metabolism connects the synthesis of nucleotides (purine and pyrimidine), amino acids (methionine, serine and glycine), S-adenosyl-methionine and folate. Ubiquinone-mediated oxidation of dihydroorotate to orotate by dihydroorotate dehydrogenase (encoded by DHODH) is a key step in pyrimidine synthesis. | 160–163 | 164 | ||
| OxPhos | Transduction of generated by the electron transport chain (ETC, also ‘respiratory chain’) into ATP synthesis by the ATP synthase (complex V), abbreviated as OxPhos. | 165 | 166 | ||
| Oxygen sensing | The electron transport and free-radical generation by ETC complexes I and III is modulated by the partial pressure of oxygen, which can limit respiration at very low partial pressures of O2. | 167–170 | – | ||
| Permeability transition | Opening of the high-conductance permeability transition pore (PTP), which dissipates membrane potential and promotes the release of intracristae and matrix-located components into the cytoplasm. | 171,172 | 173–175 | ||
| Protein import | Import, processing and folding of nuclear-encoded polypeptides from the cytoplasm by the translocator of the inner membrane (TIM) and outer membrane (TOM) complexes and associated proteins. | 176 | – | ||
| Redox homeostasis | Re-oxidation of enzymes and/or their redox cofactors (involved in anabolic and catabolic reactions) by the electron acceptors CoQ and cytochrome c (encoded by CYTC) within the mitochondrial respiratory chain, and production of NADPH by NNT. | 177,178 | – | ||
| Respiration | Electrons stored in reducing equivalents NADH and FADH2, or derived from diverse redox reactions are sequentially delivered to respiratory complex I and CoQ, or cytochrome c, respectively, to promote the reduction of molecular oxygen at cytochrome c oxidase (complex IV). | 179,180 | 181 | ||
| ROS production | Production and release of ROS (H2O2, O2•−, others) mainly at respiratory chain complexes I and III. | 182,183 | 184 | ||
| Steroidogenesis | Production of pregnanolone from cholesterol imported via IMM steroidogenic acute regulatory protein (encoded by STAR) followed by enzymatic transformation by P450ssc (encoded by CYP11A1) in the matrix. Intermediate or terminal steps for some steroids occur in the ER. Cytochrome P450 family members participate also in xenobiotic metabolism as well as bile acid and vitamin D biosynthesis. | 33,34,185,186 | 187 | ||
| Behaviours | |||||
| Antiviral signalling | Assembly of the mitochondrial antiviral signal (encoded by MAVS) adaptor protein on the OMM to potentiate downstream signalling, and activation of nuclear interferon pathways in the nucleus by mtDNA release. | 39,188 | – | ||
| Apoptotic signalling | Release of cytochrome c (encoded by CYCS), apoptosis-inducing factor (encoded by AIF), and other proteins that trigger different forms of cell death by acting on cytoplasmic and nuclear effectors. | 189,190 | – | ||
| Cristae remodelling | Dynamic remodelling of IMM cristae junctions, cristae shape and distribution via the combined action of optic atrophy 1 (encoded by OPA1) and mitochondrial contact site and cristae organizing system (MICOS) proteins. | 103,191 | 95 | ||
| DNA signalling | mtDNA extrusion in the cytoplasm, particularly in the form of oxidized mtDNA fragments via proteinaceous pores forming across the IMM and OMM, which trigger inflammasome activation. | 189,190,192,193 | 175 | ||
| Epigenetic remodelling | Transduction of mitochondrial states into changes in epigenome via several functions including metabolic intermediates, DNA release, ROS production and others. | 30,194 | – | ||
| Inter-organelle communication | Exchange of information between mitochondria and other organelles, particular the ER, where mitofusin 2 (encoded by MFN2) plays a key role in tethering organelles. | 195,196 | 197,198 | ||
| Mitochondrial dynamics | Mitochondrial fusion and fission through OMM-anchored and IMM-anchored GTPase proteins capable of merging or constricting mitochondrial membranes to enact fragmentation of larger organelles into smaller ones. |
191,199–201 | 202 | ||
| Mito–mito communication | Exchange of information between mitochondria by soluble signals (for example, ROS-induced ROS release, RIRR), by complete membrane fusion, or by physical extensions of thin protein-carrying OMM and IMM membrane protrusions (that is, nanotunnels) and trans-mitochondrial cristae alignment between energized mitochondria. | 203–206 | 207–209 | ||
| Motility | Movement of energized mitochondria across the cytoplasm via the combined action of motor and adaptor proteins interacting with cytoskeletal elements. | 6,210 | 211 | ||
| Vesicle formation | Release of MDVs destined to different cellular fates by the action of motor and accessory proteins acting on the OMM and IMM. | 212 | 213,214 | ||
a
Generation of mitochondrial membrane potential is the ‘mother’ of many other functions and behaviours, providing the driving force for the movement of ions, solutes and proteins across the IMM, the driving force for key enzymes and processes, including the phosphorylation of ADP into ATP (OxPhos). Mitochondrial features (that is, molecular components) and activities (individual enzyme and non-enzymatic activities) are too numerous to be comprehensively listed, so only functions and behaviours are included. CoQ, coenzyme Q.