Stop wasting protein—Proteasome inhibition to target diseases linked to mitochondrial import

Habich, Markus; Riemer, Jan

doi:10.15252/emmm.201910441

Cited by 6 publications

(3 citation statements)

References 11 publications

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“…Mitochondrial diseases are caused by mutations in mitochondrial DNA or nuclear DNA sequences that encode proteins relevant for mitochondrial protein biosynthesis, assembly and proper function. Mitochondrial protein functions can be affected by these mutations in many ways; they not only impair enzymatic activities, but can also lower protein stability, hamper assembly into multimeric protein complexes, or abrogate protein transport into mitochondria ( Habich and Riemer, 2019 ). The COA7 gene, also known as 1orf163 and RESA1 , encodes a mitochondria-localized protein that is involved in the assembly of mitochondrial CIV, which is the last enzyme component of the mitochondrial respiratory chain ( Martinez Lyons et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient

et al. 2021

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ObjectiveThe cytochrome c oxidase assembly factor 7 (COA7) gene encodes a protein localized to mitochondria that is involved in the assembly of mitochondrial respiratory chain complex IV. Here, we report the clinical, genetic and biochemical analysis of a female patient with suspected mitochondrial disorder and novel variants in COA7, that presented with a considerably different phenotype and age of onset than the five COA7 patients reported to date.MethodsWe performed trio-exome sequencing in the affected patient and both parents. To verify the pathogenicity of the detected variants in COA7, mitochondrial enzyme activities and oxygen consumption rate were investigated in fibroblasts of the patient and her parents.ResultsA Chinese girl was referred at 9 months of age with a history of developmental delay and regression since 3 months of age. In the following months, she lost previously acquired skills and developed progressive spasticity of the lower extremities. Trio-exome sequencing revealed compound heterzygous variants in COA7 (c.511G > A/p.Ala171Thr and c.566A > G/p.Asn189Ser). Functional validation experiments revealed isolated complex IV deficiency and a significantly reduced mitochondrial respiration rate in patient-derived fibroblasts.InterpretationHitherto, characteristic features of COA7 patients were described as slowly progressing neuropathy and spinocerebellar ataxia, starting at the toddler age and progressing into adulthood. In contrast, our patient was reported to show developmental delay from 3 months of age, which was found to be due to a rapidly progressive encephalopathy and brain atrophy seen at 9 months of age. Unexpectedly, the genetic investigation revealed a COA7-associated mitochondrial disease, which was confirmed functionally. Thus, this report broadens the genetic and clinical spectrum of this heterogeneous mitochondriopathy and highlights the value of the presented unbiased approach.

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Section: Discussionmentioning

confidence: 99%

Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient

et al. 2021

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“…Recent work proposed to repurpose proteasome-inhibiting drugs as a way to increase the import of such proteins into the mitochondria and thus recover their functions [ 134 ]. Possibly also other mutant mitochondrial proteins could be rescued by this approach [ 238 ]. Improving our understanding of the cytosolic quality control of mitochondrial biogenesis opens new possibilities to modulate organelle function.…”

Section: Discussionmentioning

confidence: 99%

Cytosolic Quality Control of Mitochondrial Protein Precursors—The Early Stages of the Organelle Biogenesis

Lenkiewicz

Krakowczyk

Brągoszewski

2021

IJMS

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With few exceptions, proteins that constitute the proteome of mitochondria originate outside of this organelle in precursor forms. Such protein precursors follow dedicated transportation paths to reach specific parts of mitochondria, where they complete their maturation and perform their functions. Mitochondrial precursor targeting and import pathways are essential to maintain proper mitochondrial function and cell survival, thus are tightly controlled at each stage. Mechanisms that sustain protein homeostasis of the cytosol play a vital role in the quality control of proteins targeted to the organelle. Starting from their synthesis, precursors are constantly chaperoned and guided to reduce the risk of premature folding, erroneous interactions, or protein damage. The ubiquitin-proteasome system provides proteolytic control that is not restricted to defective proteins but also regulates the supply of precursors to the organelle. Recent discoveries provide evidence that stress caused by the mislocalization of mitochondrial proteins may contribute to disease development. Precursors are not only subject to regulation but also modulate cytosolic machinery. Here we provide an overview of the cellular pathways that are involved in precursor maintenance and guidance at the early cytosolic stages of mitochondrial biogenesis. Moreover, we follow the circumstances in which mitochondrial protein import deregulation disturbs the cellular balance, carefully looking for rescue paths that can restore proteostasis.

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“…Unlike the proteins bound to the mitochondrial membranes or matrix by dedicated import machinery constituting a plethora of proteins, the IMS proteins are brought in and retained in the IMS by a unique pathway called the disulphide relay pathway [ 2 , 3 ]. The import of the IMS targeted proteins is coupled to their folding and oxidation by the disulphide relay pathway [ 4 , 5 ]. MIA40 (Mitochondrial intermembrane space import and assembly protein 40)/CHCHD4 (coiled-coil-helix-coiled-coil-helix-domain containing 4) and ALR (Augmenter of liver regeneration) are the two important known proteins of this pathway [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Glutathionylated and Fe–S cluster containing hMIA40 (CHCHD4) regulates ROS and mitochondrial complex III and IV activities of the electron transport chain

et al. 2020

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Human MIA40, an i nter m embrane s pace (IMS) import receptor of mitochondria harbors twin CX9C motifs for stability while its CPC motif is known to facilitate the import of IMS bound proteins. Site-directed mutagenesis complemented by MALDI on in vivo hMIA40 protein shows that a portion of MIA40 undergoes reversible S-glutathionylation at three cysteines in the twin CX9C motifs and the lone cysteine 4 residue. We find that HEK293T cells expressing hMIA40 mutant defective for glutathionylation are compromised in the activities of complexes III and IV of the Electron Transport Chain (ETC) and enhance Reactive Oxygen Species (ROS) levels. Immunocapture studies show MIA40 interacting with complex III. Interestingly, glutathionylated MIA40 can transfer electrons to cytochrome C directly. However, Fe–S clusters associated with the CPC motif are essential to facilitate the two-electron to one-electron transfer for reducing cytochrome C. These results suggest that hMIA40 undergoes glutathionylation to maintain ROS levels and for optimum function of complexes III and IV of ETC. Our studies shed light on a novel post-translational modification of hMIA40 and its ability to act as a redox switch to regulate the ETC and cellular redox homeostasis.

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Stop wasting protein—Proteasome inhibition to target diseases linked to mitochondrial import

Cited by 6 publications

References 11 publications

Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient

Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient

Cytosolic Quality Control of Mitochondrial Protein Precursors—The Early Stages of the Organelle Biogenesis

Glutathionylated and Fe–S cluster containing hMIA40 (CHCHD4) regulates ROS and mitochondrial complex III and IV activities of the electron transport chain

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