Molecular mechanism of mitochondrial respiratory chain assembly and its relation to mitochondrial diseases

Mukherjee, Sourav; Ghosh, Alok

doi:10.1016/j.mito.2020.04.002

Cited by 38 publications

(18 citation statements)

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“…The ETC machinery is encoded by both the nuclear DNA (nDNA) (80 proteins) and mitochondrial DNA (mtDNA) (13 proteins). Nuclear-encoded proteins (roughly 70% of total mitochondrial proteins) also have functions in ETC supercomplex (or respirasome) assembly [ 19 ] and in mtDNA replication and repair [ 20 ]. Therefore, nuclear and mitochondrial gene expressions need to be tightly coordinated to ensure effective mitochondrial functioning.…”

Section: Role Of the Mitochondrial Etc And Oxphos In Physiology Anmentioning

confidence: 99%

“…Complex I is composed of 14 conserved core subunits, encoded by both the mitochondrial and nuclear DNAs, and of at least 30 additional nuclear-encoded accessory subunits. Half the core subunits (ND1, ND2, ND3, ND4, ND4L, ND5, ND6) are mitochondria-encoded and constitute the membrane-embedded arm, while the other half (NDUFS1, NDUFV1, NDUFV2, NDUFS2, NDUFS3, NDUFS8, NDUFS7) are nuclear-encoded and constitute the peripheral arm [ 19 , 29 , 30 ]. Complex I is the main target of the currently-identified mtDNA mutations.…”

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

“…Electrons from FADH2 are then transferred sequentially to SDHB and to ubiquinone at the inner membrane-embedded site formed by SDHC and SDHD. Contrary to complexes I, III, and IV, complex II-mediated electron transport is not accompanied by proton translocation into the mitochondrial intermembrane space [ 19 , 59 ].…”

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

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Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Nakhle

Rodriguez

Vignais

2020

IJMS

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Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.

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Section: Role Of the Mitochondrial Etc And Oxphos In Physiology Anmentioning

confidence: 99%

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

See 1 more Smart Citation

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Nakhle

Rodriguez

Vignais

2020

IJMS

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“…The products of several nuclear-encoded genes (UQCRB, UQCRC1, UQCRC2, CYC1, UQCRFS1, UQCRH, UQCRQ, UQCR10, UQCR11) and one mitochondrial-encoded gene (MT-CYB) form the primary subunits of the CIII which ultimately congregated by different assembly factors (BCS1L, LYRM7, TTC19, UQCC1, UQCC2, UQCC3) resulting in the functional homodimer CIII (9,13).…”

Section: Discussionmentioning

confidence: 99%

“…It is synthesized as a pre-protein in the cytosol and post-translationally imported into mitochondria where it turns to its mature protein after two cleavage episodes (7). The matured protein with its covalently attached heme c1 at N terminal of the protein poses in a unique topology within the CIII and is functional to accept electrons from the Rieske protein and pass it to cytochrome c (7)(8)(9). Despite the fact that the function of CIII structural proteins including cyt c 1 is well understood, the genotype-phenotype correlation of many of these proteins are yet to be classi ed.…”

Section: Introductionmentioning

confidence: 99%

Complex III Mitochondrial Leukoencephalopathy Masquerading Acute Demyelinating Syndrome Due to a Novel Variant in CYC1

Heidari

Rasoulinezhad

Pak

et al. 2021

Preprint

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Background Complex III (CIII) is the third out of five mitochondrial respiratory chain complexes residing at the mitochondrial inner membrane. The assembly of 10 subunits encoded by nuclear DNA and one by mitochondrial DNA result in the functional CIII which transfers electrons from ubiquinol to cytochrome c. Deficiencies of CIII are among the least investigated mitochondrial disorders and thus clinical spectrum of patients with mutations in CIII is not well defined. Resultswe report on a 10-year-old girl born to consanguineous Iranian parents presenting with acute neurological deficits reminiscent of acquired demyelination, mainly acute bilateral vision loss, who was ultimately confirmed to have a novel homozygous missense variant, c.949C>T; p.(Arg317Trp) in complex III of the mitochondrial chain. Sanger sequencing confirmed the segregation of this variant with disease in the family. ConclusionWe present a patient with a mitochondrial leukoencephalopathy due to complex III deficiency that manifested with features suggestive of an acquired demyelinating syndrome. The effect of this variant on the protein structure was shown in-silico. Our findings, not only expand the clinical spectrum due to defects in CYC1 gene but also highlight that mitochondrial disease should be considered in children with acute CNS demyelination.

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Expanding phenotype heterogeneity of NARS2 by presenting subdural hematoma and parenchymal hemorrhage

Khodaeian,

Bitarafan,

Garrousi

et al. 2023

Clinical Laboratory Analysis

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BackgroundNARS2 encodes mitochondrial Asparaginyl‐tRNA Synthetase 2, which catalyzes the aminoacylation of tRNA‐Asn in the mitochondria. To date, 24 variants have been reported in NARS2 gene in 35 patients. The phenotypic variability of NARS2‐associated disorder is broad, ranging from neurodevelopmental disorders to hearing loss. In this study, we report some novel imaging findings in an Iranian patient suffering from epileptic encephalopathy, caused by a previously reported variant, c.500A > G; p.(His167Arg), in NARS2.MethodsThe spectrum of clinical manifestations of two Iranian patients was investigated and genetic analysis was performed by Whole‐exome sequencing (WES). Additionally, we also reviewed the literature and summarized the phenotypes of previously reported patients with variants in the NARS2 gene.ResultsHere, we present the phenotypic and genetic features of 2 unrelated Iranian infants presented with neurodevelopmental delay, seizures, hearing impairment, feeding problems, elevated serum lactate levels in addition to subdural hematoma and cerebral parenchymal hemorrhage in the brain magnetic resonance imaging (MRI) of one of the patients. Genetic analysis revealed a biallelic missense variant in NARS2: c.500A > G; p.(His167Arg). We described the subdural hematoma and cerebral parenchymal hemorrhage of the brain for the first time.ConclusionsOur study provides new clinical findings, subdural hematoma, and parenchymal hemorrhage, in NARS2‐related disorders. Our findings along with previous studies provide more evidence of the clinical presentation of the disease caused by pathogenic variants in NARS2. Expanding the clinical spectrum increases the diagnostic rate of molecular testing and improves the quality of counseling for at‐risk couples.

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Molecular mechanism of mitochondrial respiratory chain assembly and its relation to mitochondrial diseases

Cited by 38 publications

References 263 publications

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Complex III Mitochondrial Leukoencephalopathy Masquerading Acute Demyelinating Syndrome Due to a Novel Variant in CYC1

Expanding phenotype heterogeneity of NARS2 by presenting subdural hematoma and parenchymal hemorrhage

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