Identifying patient-centered outcomes in progressive familial intrahepatic cholestasis: Results from IMPACT.
Authors: Squires JE, Lubke GH, Ventura E, Perez A, Hertel PM, Perito ER, Bull L, Kochanowsky M
Journal: Journal of pediatric gastroenterology and nutrition
mental health
psychology
open access
Abstract
Mitochondria are essential organelles responsible for converting the energy derived from nutrients into adenosine triphosphate (ATP), a high-energy molecule readily used by the cells, through a process known as oxidative phosphorylation (OXPHOS; Fig. ) []. This intricate process occurs within the inner mitochondrial membrane (IMM), where four multi-protein complexes (Complexes I–IV, CI-IV) and the mitochondrial (Complex V, CV), along with the mobile electron carriers cytochrome c and coenzyme Q, coordinate the transfer of electrons to molecular oxygen through the electron transport system (ETS) []. As electrons move through the ETS, protons are pumped from the mitochondrial matrix into the intermembrane space, establishing an electrochemical gradient (Dy) which is then harnessed by ATP synthase to generate ATP from ADP and inorganic phosphate [, ]. Beyond energy conversion, mitochondria play central roles in numerous other cellular functions, including apoptosis, calcium buffering, redox balance, and the biosynthesis of essential prosthetic groups for several proteins, such as heme, steroids, and iron-sulfur clusters. These diverse functions are critically dependent on the integrity of the OXPHOS system, making it a key node of cellular physiology []. . The process involves a series of protein complexes located in the inner mitochondrial membrane (IMM), specifically, complexes I to IV of the electron transport chain, and complex V or ATP synthase. Complex I (NADH:coenzyme Q oxidoreductase) carires out the transfer of electrons from NADH to coenzyme Q10 (CoQ), reducing it from its oxidized form (ubiquinone) to its reduced form (ubiquinol, QH₂), while contributing to the formation of a proton gradient. Complex II (succinate-CoQ oxidoreductase) bridges the TCA cycle and the electron transport chain by oxidizing succinate and reducing CoQ to QH₂. Complex III (ubiquinol-cytochrome c oxidoreductase) transfers electrons from ubiquinol to cytochrome c, continuing the buildup of the proton gradient across the membrane. Complex IV (cytochrome c oxidase) transfers electrons to molecular oxygen, forming water and further contributing to the proton motive force. Finally, complex V (ATP synthase) uses the energy stored in the transmembrane proton gradient to drive the synthesis of ATP from ADP and inorganic phosphate through a mechanical rotation mechanism. OMM: outer mitochondrial membrane; IMS: intermembrane space; IMM: inner mitochondrial membrane; e: electron; P: phosphate; CoQ: coenzyme Q; Cyt c: cytochrome c.
. Mitochondrial disorders present with diverse symptoms, that can affect any organ or tissue. Clinical features are typically multisystemic and may be broadly categorized into neurological and non-neurological manifestations, with significant variability between individuals. Figure prepared with Biorender. Defects in OXPHOS can arise from mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), reflecting the dual-genomic origin of the mitochondrial proteome []. The mitochondrial genome is a small circular DNA which is present in hundreds to thousands of copies in each cell. The multicopy nature of mtDNA implies that mutations arising in it only affect part of the molecules (a condition known as heteroplasmy) and remain silent until they exceed a certain threshold [–]. This has important implications for the therapy, as interventions aimed at reducing the mutational burden below the threshold may be beneficial to the patients. It should be noted, however, that also homoplasmic mutations, i.e. in which all the mtDNA molecules are mutated, may cause mitochondrial diseases. MtDNA encodes 13 core subunits of the ETS, along with 22 tRNAs and 2 rRNAs required for mitochondrial protein translation. The vast majority of the mitochondrial proteome is encoded by nDNA, synthesized in the cytoplasm, and imported into mitochondria through an ATP-dependent mechanism [, ].
. Mitochondrial disorders present with diverse symptoms, that can affect any organ or tissue. Clinical features are typically multisystemic and may be broadly categorized into neurological and non-neurological manifestations, with significant variability between individuals. Figure prepared with Biorender. Defects in OXPHOS can arise from mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), reflecting the dual-genomic origin of the mitochondrial proteome []. The mitochondrial genome is a small circular DNA which is present in hundreds to thousands of copies in each cell. The multicopy nature of mtDNA implies that mutations arising in it only affect part of the molecules (a condition known as heteroplasmy) and remain silent until they exceed a certain threshold [–]. This has important implications for the therapy, as interventions aimed at reducing the mutational burden below the threshold may be beneficial to the patients. It should be noted, however, that also homoplasmic mutations, i.e. in which all the mtDNA molecules are mutated, may cause mitochondrial diseases. MtDNA encodes 13 core subunits of the ETS, along with 22 tRNAs and 2 rRNAs required for mitochondrial protein translation. The vast majority of the mitochondrial proteome is encoded by nDNA, synthesized in the cytoplasm, and imported into mitochondria through an ATP-dependent mechanism [, ].