Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms

Yazdani, Mazyar

doi:10.1007/s12035-024-03938-7

Cited by 2 publications

References 149 publications

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Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease

Morcillo,

Kabra,

Velasco

et al. 2024

Cell Death Dis

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Genetic mutations causing primary mitochondrial disease (i.e those compromising oxidative phosphorylation [OxPhos]) resulting in reduced bioenergetic output display great variability in their clinical features, but the reason for this is unknown. We hypothesized that disruption of the communication between endoplasmic reticulum (ER) and mitochondria at mitochondria-associated ER membranes (MAM) might play a role in this variability. To test this, we assayed MAM function and ER-mitochondrial communication in OxPhos-deficient cells, including cybrids from patients with selected pathogenic mtDNA mutations. Our results show that each of the various mutations studied indeed altered MAM functions, but notably, each disorder presented with a different MAM “signature”. We also found that mitochondrial membrane potential is a key driver of ER-mitochondrial connectivity. Moreover, our findings demonstrate that disruption in ER-mitochondrial communication has consequences for cell survivability that go well beyond that of reduced ATP output. The findings of a “MAM-OxPhos” axis, the role of mitochondrial membrane potential in controlling this process, and the contribution of MAM dysfunction to cell death, reveal a new relationship between mitochondria and the rest of the cell, as well as providing new insights into the diagnosis and treatment of these devastating disorders.

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Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease

Morcillo,

Kabra,

Velasco

et al. 2024

Cell Death Dis

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Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in theC. elegans uaDf5animal model

Mendel,

Matsuno,

et al. 2024

Preprint

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Single large scale mitochondrial DNA (mtDNA) deletions (SLSMD) underlie a range of sporadic or maternally inherited primary mitochondrial diseases having significant morbidity and mortality, including Pearson syndrome, Kearns-Sayre Syndrome, or Chronic Progressive External Ophthalmoplegia. Therapeutic development has been hindered by limited existing knowledge on mtDNA quality control and a lack of SLSMD animal models. To address this challenge, we utilized the C. elegans heteroplasmic SLSMD strain, uaDf5, to objectively screen for potential therapies. As mitophagy modulation has been implicated in mtDNA homeostasis, we screened a library of mitophagy modulating compounds to determine their comparative effects to rescue mitochondrial unfolded protein (UPRmt) stress induction in in uaDf5 SLSMD worms. Interestingly, Thiamine was discovered to be an effective positive control, significantly reducing mitochondrial stress in this model. Two lead therapeutic candidates from the mitophagy library screen were Hemin and Celastrol (Tripterin). Celastrol is a mitophagy activating anti-inflammatory and metabolic modifying natural product derived compound, that rescued multiple fitness outcomes (thrashing, development, survival) and reduced the mitochondrial stress in uaDf5 animals in a mitophagy-dependent fashion. This study highlights the utility of the uaDf5 worm model to enable preclinical identification of therapeutic candidate leads for SLSMD-based heteroplasmic mtDNA diseases and identifies possible therapeutic candidates that serve as mitophagy modulators to improve health and specifically reduce heteroplasmy levels in SLSMD diseases.

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Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms

Cited by 2 publications

References 149 publications

Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease

Aberrant ER-mitochondria communication is a common pathomechanism in mitochondrial disease

Mitophagy modulation rescues single large-scale mitochondrial DNA deletion (SLSMD) disease symptoms in theC. elegans uaDf5animal model

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