Mitochondrial developmental encephalopathy with bilateral optic neuropathy related to homozygous variants in<scp><i>IMMT</i></scp>gene

Marco‐Hernández, Ana Victoria; Tomás‐Vila, Miguel; Montoya-Filardi, A.; Barranco-González, H.; Padilla, Juan Jesus Vilchez; Azorı́n, Inmaculada; Dura, Patricia Smeyers; Monfort, Sandra; Castellano, Inmaculada Pitarch; Martínez-Castellano, F

doi:10.1111/cge.14093

Cited by 10 publications

(7 citation statements)

References 45 publications

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“…However, the probability of an inner mitochondrial membrane (IMM) protein serving as a signaling platform of mitophagy has not been excluded 34 , 52 . Here, we found that IMMT was identified as a substrate of KLHL9/KLHL13/CUL3 complex, which is an essential protein situated on IMMs and interacts with several OMM proteins and orchestrates mitochondrial architecture 53 – 55 . This work has revealed that the mitochondrial stress induced upon B. pseudomallei infection may precipitate a mitochondrial integrity loss and OMM severing, and in turn contributes to a possibility for IMMT exposure and ubiquitination, which is involved with Parkin-independent, DRP1 mediation.…”

Section: Discussionmentioning

confidence: 95%

Burkholderia pseudomallei BipD modulates host mitophagy to evade killing

Nan,

Rao,

Tang

et al. 2024

Nat Commun

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Mitophagy is critical for mitochondrial quality control and function to clear damaged mitochondria. Here, we found that Burkholderia pseudomallei maneuvered host mitophagy for its intracellular survival through the type III secretion system needle tip protein BipD. We identified BipD, interacting with BTB-containing proteins KLHL9 and KLHL13 by binding to the Back and Kelch domains, recruited NEDD8 family RING E3 ligase CUL3 in response to B. pseudomallei infection. Although evidently not involved in regulation of infectious diseases, KLHL9/KLHL13/CUL3 E3 ligase complex was essential for BipD-dependent ubiquitination of mitochondria in mouse macrophages. Mechanistically, we discovered the inner mitochondrial membrane IMMT via host ubiquitome profiling as a substrate of KLHL9/KLHL13/CUL3 complex. Notably, K63-linked ubiquitination of IMMT K211 was required for initiating host mitophagy, thereby reducing mitochondrial ROS production. Here, we show a unique mechanism used by bacterial pathogens that hijacks host mitophagy for their survival.

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Section: Discussionmentioning

confidence: 95%

Burkholderia pseudomallei BipD modulates host mitophagy to evade killing

Nan,

Rao,

Tang

et al. 2024

Nat Commun

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“…These results also demonstrate the importance of functional MIC60 in a way that relates back to IMMT mutations found in patients with Parkinson’s disease. In addition, another study identified two consanguineous cousins presenting with developmental encephalopathy that was likely caused by a homozygous mutation in IMMT ( 28 ). Indeed, defects in mitochondrial function commonly manifest in relation to neurodegenerative disorders ( 29 , 30 , 31 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic ablation ofImmtinduces a lethal disruption of the MICOS complex

Rockfield,

Turnis,

Rodriguez-Enriquez

et al. 2024

Life Sci. Alliance

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The mitochondrial contact site and cristae organizing system (MICOS) is important for crista junction formation and for maintaining inner mitochondrial membrane architecture. A key component of the MICOS complex is MIC60, which has been well studied in yeast and cell culture models. However, only one recent study has demonstrated the embryonic lethality of losingImmt(the gene encoding MIC60) expression. Tamoxifen-inducible ROSA-CreERT2–mediated deletion ofImmtin adult mice disrupted the MICOS complex, increased mitochondria size, altered cristae morphology, and was lethal within 12 d. Pathologically, these mice displayed defective intestinal muscle function (paralytic ileus) culminating in dehydration. We also identified bone marrow (BM) hypocellularity inImmt-deleted mice, although BM transplants from wild-type mice did not improve survival. Altogether, this inducible mouse model demonstrates the importance of MIC60 in vivo, in both hematopoietic and non-hematopoietic tissues, and provides a valuable resource for future mechanistic investigations into the MICOS complex.

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“…49,50 IMMT/MIC60 mutations were found in Parkinson's disease patients 51 and mitochondrial developmental encephalopathy with bilateral optic neuropathy. 52 What is surprising is that different proteins as well as different mutations of various MICOS proteins manifest into vastly different phenotypes and syndromes. This shows the importance of mitochondrial membrane structure for proper health and functionality.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in MICOS13/MIC13 cause severe form of mitochondrial encephalopathy with liver dysfunction 49,50 . IMMT / MIC60 mutations were found in Parkinson's disease patients 51 and mitochondrial developmental encephalopathy with bilateral optic neuropathy 52 . What is surprising is that different proteins as well as different mutations of various MICOS proteins manifest into vastly different phenotypes and syndromes.…”

Section: Discussionmentioning

confidence: 99%

A X‐linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria‐like phenotypes

Peifer‐Weiß,

Kurban,

David

et al. 2023

Clinical Genetics

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APOO/MIC26 is a subunit of the MICOS complex required for mitochondrial cristae morphology and function. Here, we report a novel variant of the APOO/MIC26 gene that causes a severe mitochondrial disease with overall progeria‐like phenotypes in two patients. Both patients developed partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies. The patients died at an early age of 12 or 18 months. Exome sequencing revealed a mutation (NM_024122.5): c.532G>T (p.E178*) in the APOO/MIC26 gene that causes a nonsense mutation leading to the loss of 20 C‐terminal amino acids. This mutation resulted in a highly unstable and degradation prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells. We conclude that the novel mutation found in the APOO/MIC26 gene is a loss‐of‐function mutation impairing mitochondrial morphology and cristae morphogenesis.

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Mitochondrial developmental encephalopathy with bilateral optic neuropathy related to homozygous variants inIMMTgene

Cited by 10 publications

References 45 publications

Burkholderia pseudomallei BipD modulates host mitophagy to evade killing

Burkholderia pseudomallei BipD modulates host mitophagy to evade killing

Genetic ablation ofImmtinduces a lethal disruption of the MICOS complex

A X‐linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria‐like phenotypes

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