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Regulation of Antiviral Immunity by Mitochondrial Dynamics
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Mohsin Khan, Hasan Imam, Saiful Anam Mir
Influenza A virus (IAV) is a major concern for morbidity and economic loss. Previous study explains the promotion of ULK1 phosphorylation and induction of mitophagy during IAV infection. This event is governed by NOD2 (Nucleotide Binding Oligomerization Domain Containing) and RIPK2 (Receptor interacting protein kinase 2) that respond to IAV infection. In Ripk2-/- cells, defective mitophagy was found and this defect leads to trigger inflammasome activation. Accumulation of damaged mitochondria is responsible for higher inflammation and therefore indicates that mitochondrial quality control is required to reduce inflammasome activation and IL-18 production during IAV infection. In case of IAV infection, mitophagy is Parkin independent and mediated by S555 phosphorylation of ULK1. Studies however indicate that NOD2-RIPK2 signaling mediated protection against IAV is mitophagy dependent. IAV protein PB1-F2 binds to MAVS and affects interferon synthesis. PB1-F2 leads to the reduction of mitochondrial membrane potential via translocation to mitochondrial inner membrane space through TOM40 channel. PB1-F2 also regulates innate immune response, triggers mitochondrial fragmentation and activation of NLRP3 inflammasome. C-terminal domain of PB1-F2 is required for regulation of mitochondrial function (Lupfer et al., 2013; Varga et al., 2012; Yoshizumi et al., 2014).
Omentin-1 promotes mitochondrial biogenesis via PGC1α-AMPK pathway in chondrocytes
Published in Archives of Physiology and Biochemistry, 2023
Zhigang Li, Yao Zhang, Fengde Tian, Zihua Wang, Haiyang Song, Haojie Chen, Baolin Wu
The mitochondrion is the "powerhouse" in eukaryotic cells. Mitochondrial biogenesis is the process of increasing cellular metabolic capacity, featured with the synthesis of enzymes for both glycolysis and oxidative phosphorylation (Jornayvaz and Shulman 2010). An efficient mitochondrial biogenesis needs the import of nuclear protein as well as mitochondrial replication, mitochondrial fusion and fission (Nunnari and Suomalainen 2012). Mitochondria in mammalian cells contain more than 1500 proteins, but only 13 proteins are coded in mitochondrial DNA, a majority of them are synthesised from nuclear DNA coding genes. Various mitochondrial molecular markers are used to study the mitochondrial regulation in eukaryotes. Translocase of the outer membrane (TOM) complex is a membrane-bound translocator vital to import mitochondrial precursors, and TOM complex includes several subunits including TOM20, TOM40 and TOM70 and is secured by TOM5, TOM6, TOM7, etc. (Ahting et al.1999). Several subunits of mitochondrial ATP synthases are also used as the markers of functional mitochondria, including ATPA, ATP5C1, ATPD and other subunits. The electron transport chain (ETC) located within the mitochondrial inner membrane composes of four protein complexes. Succinate dehydrogenase complex iron-sulfur subunit B (SDHB) links the pathways of Krebs cycle and oxidative phosphorylation. Mitochondrial DNA encoded subunits (MTCO1, MTCO2, MTCO3) are important subunits of complex IV (Zhao et al.2019).
Pharmacogenomics of drugs used to treat brain disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
Adjacent to the APOE locus (19q13.2) and in linkage disequilibrium with APOE is the TOMM40 gene. A poly T repeat in an intronic polymorphism (rs10524523) (intron 6) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of Aβ and other proteins into mitochondria, has been implicated in AD pathogenesis and PGx. There are 3 allele groups for rs10524523 (‘523ʹ), based on the number of ‘T’-residues: ‘Short’ (S, T ≤ 19), ‘Long’ (L, 20 ≤ T ≤ 29) and ‘Very Long’ (VL, T ≥ 30). Longer lengths of rs10524523 are associated with a higher risk for late-onset AD (LOAD). S/VL and VL/VL are the only TOMM40 poly T genotypes which interact with all major APOE genotypes; in contrast, the APOE-4/4-TOMM40-L/L association is unique, representing approximately 30% of APOE-4/4 carriers. TOMM40 poly T-S/S carriers are the best responders, VL/VL and S/VL carriers are intermediate responders, and L/L carriers are the worst responders to treatment; patients harboring a large (L) number of poly T repeats in intron 6 of the TOMM40 gene (L/L or S/L genotypes) in haplotypes associated with APOE-4 are the worst responders to treatment; patients with short (S) TOMM40 poly T variants (S/S genotype), and to a lesser extent S/VL and VL/VL carriers, in haplotypes with APOE-3 are the best responders to treatment. In 100% of the cases, the L/L genotype is exclusively associated with the APOE-4/4 genotype, and this haplotype (4/4-L/L) is probably responsible for early onset of the disease, a faster cognitive decline, and a poor response to different treatments [85].
Misconnecting the dots: altered mitochondrial protein-protein interactions and their role in neurodegenerative disorders
Published in Expert Review of Proteomics, 2020
Mara Zilocchi, Mohamed Taha Moutaoufik, Matthew Jessulat, Sadhna Phanse, Khaled A. Aly, Mohan Babu
In this section, we will first discuss the pathological PPIs of mt-associated proteins and their connectivity to PD. Mt sickness resides at the core of NDs, and this is in large part attributed to PPI alterations that engage in pathological associations, triggering and/or advancing NDs. In PD, most patients sporadically develop the disorder with no family history, but some cases are inherited (familial) due to mutations in both gene copies (autosomal recessive PD) or one gene copy (autosomal dominant PD). Many PD-altered genes code for proteins that associate with mt to mediate pathological PPIs. Alpha-synuclein (α-Syn) is a versatile pre-synaptic protein that modulates a repertoire of functions in neurons, such as the regulation of neurotransmitter release, synaptic function and plasticity [150]. Aside from its role in healthy mt, a strong body of research links α-Syn to PD, as PD-associated α-Syn is rewired to interact with several mt proteins that mediate its internalization into the mt matrix in a fashion that does not take place in healthy neurons. In particular, TOMM40 moderates α-Syn intake via direct interaction [151], triggering α-Syn association with TOMM20 to accumulate α-Syn in the mt matrix, and subsequent interaction with complex I (NADH: ubiquinone oxidoreductase), the first of five complexes in the respiratory chain involved in energy metabolism through NADH oxidation and electron transfer to coenzyme Q. Complex I and α-Syn interaction is mediated by the N-terminal domain of α-Syn, resulting in reduction of complex I activity in PD.