Biallelic variants in <i>COX4I1</i> associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures

Pillai, Nishitha R.; AlDhaheri, Noura S.; Ghosh, Rajarshi; Lim, Jaehyung; Streff, Haley; Nayak, Anuranjita; Graham, Brett H.; Hanchard, Neil A.; Elsea, Sarah H.; Scaglia, Fernando

doi:10.1002/ajmg.a.61288

Cited by 12 publications

(4 citation statements)

References 29 publications

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“…COX is an enzyme of the mitochondrial respiratory chain which plays a key role in mitochondrial oxidative phosphorylation through a transfer of electrons from cytochrome c to oxygen, leading to the induction of the proton electrochemical gradient and mitochondrial membrane potential (Li, Park, Deng, & Bai, ). A clinical study has shown that the defective production of COX causes myopathy and Leigh syndrome (Pillai et al, ). Mutation in the human COX4I1 gene induces short stature, poor weight gain, and chromosomal breaks (Abu‐Libdeh et al, ).…”

Section: Discussionmentioning

confidence: 99%

Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

et al. 2020

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Mesenchymal stem cells (MSCs) are a popular cell source for stem cell‐based therapy. However, continuous ex vivo expansion to acquire large amounts of MSCs for clinical study induces replicative senescence, causing decreased therapeutic efficacy in MSCs. To address this issue, we investigated the effect of melatonin on replicative senescence in MSCs. In senescent MSCs (late passage), replicative senescence decreased mitophagy by inhibiting mitofission, resulting in the augmentation of mitochondrial dysfunction. Treatment with melatonin rescued replicative senescence by enhancing mitophagy and mitochondrial function through upregulation of heat shock 70 kDa protein 1L (HSPA1L). More specifically, we found that melatonin‐induced HSPA1L binds to cellular prion protein (PrPC), resulting in the recruitment of PrPC into the mitochondria. The HSPA1L‐PrPC complex then binds to COX4IA, which is a mitochondrial complex IV protein, leading to an increase in mitochondrial membrane potential and anti‐oxidant enzyme activity. These protective effects were blocked by knockdown of HSPA1L. In a murine hindlimb ischemia model, melatonin‐treated senescent MSCs enhanced functional recovery by increasing blood flow perfusion, limb salvage, and neovascularization. This study, for the first time, suggests that melatonin protects MSCs against replicative senescence during ex vivo expansion for clinical application via mitochondrial quality control.

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Section: Discussionmentioning

confidence: 99%

Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

et al. 2020

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“…In most cell types, COX4I2 expression is induced in hypoxia [203,204], but it is constitutively expressed in pulmonary and pancreatic acinar cells [202,205]. In addition, mutations in the gene encoding the ubiquitous isoform, COX4I1, have also been associated with poor growth and Fanconi anemia [206], and with Leigh-like syndrome [207]. COX5A forms an early subassembly complex with COX4 [186].…”

Section: Mutations In Complex IV Structural Subunitsmentioning

confidence: 99%

Mitochondrial disorders of the OXPHOS system

2020

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Mitochondrial disorders are amongst the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system (OXPHOS). OXPHOS is composed of the electron transport chain (ETC), formed by four multimeric enzymes and two mobile electron carriers, plus an ATP synthase (also called complex V). The ETC performs the redox reactions involved in cellular respiration while generating the proton motive force used by complex V to synthesize ATP. OXPHOS biogenesis involves multiple steps, starting from the expression of genes encoded in physically separated genomes, namely the mitochondrial and nuclear DNA, to the coordinated assembly of components and cofactors building each individual complex and eventually the supercomplexes. The genetic cause underlying around half of the diagnosed mitochondrial disease cases is currently known. Many of these cases result from pathogenic variants in genes encoding structural subunits or additional factors directly involved in the assembly of the ETC complexes. Here we review the historical and most recent findings concerning the clinical phenotypes and the molecular pathological mechanisms underlying this particular group of disorders.

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“…Mutations in the respective genes have been linked to mitochondrial diseases. While COX4-1 patients [63,64] present, for example, short stature and Leigh-like syndrome, COX5A mutations have been associated with psychomotoric delay, cortical atrophy, or lactic acidemia [65,66]. Although PET117 has been reported as a COX15 interactor [67], it has been also defined as an interactor of the late assembly factor PET100 [48,68].…”

Section: Factors Assisting Early Cox Assembly Stepsmentioning

confidence: 99%

Cytochrome c oxidase biogenesis – from translation to early assembly of the core subunit COX1

2023

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Mitochondria are the powerhouses of the cell as they produce the majority of ATP with their oxidative phosphorylation (OXPHOS) machinery. The OXPHOS system is composed of the F1Fo ATP synthase and four mitochondrial respiratory chain complexes, the terminal enzyme of which is the cytochrome c oxidase (complex IV) that transfers electrons to oxygen, generating water. Complex IV comprises of 14 structural subunits of dual genetic origin: while the three core subunits are mitochondrial encoded, the remaining constituents are encoded by the nuclear genome. Hence, the assembly of complex IV requires the coordination of two spatially separated gene expression machinery. Recent efforts elucidated an increasing number of proteins involved in mitochondrial gene expression, which are linked to complex IV assembly. Additionally, several COX1 biogenesis factors have been intensively biochemically investigated and an increasing number of structural snapshots shed light on the organization of macromolecular complexes such as the mitoribosome or the cytochrome c oxidase. Here, we focus on COX1 translation regulation and highlight the advanced understanding of early steps during COX1 assembly and its link to mitochondrial translation regulation.

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Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures

Abstract: Autosomal recessive COX4I1 deficiency has been previously reported in a single individual with a homozygous pathogenic variant in COX4I1, who presented with short stature, poor weight gain, dysmorphic features, and features of Fanconi anemia.

Cited by 12 publications

References 29 publications

Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

Melatonin suppresses senescence‐derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway

Mitochondrial disorders of the OXPHOS system

Cytochrome c oxidase biogenesis – from translation to early assembly of the core subunit COX1

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