Altered Mitochondrial Protein Homeostasis and Proteinopathies

Jishi, Aya; Qi, Xin

doi:10.3389/fnmol.2022.867935

Cited by 8 publications

(4 citation statements)

References 181 publications

(215 reference statements)

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“…Mitochondria dysfunction has been repeatedly reported in heart diseases and neurological disorders ( 40 – 45 ), but the underlying mechanisms are still not fully understood ( 43 , 46 – 50 ). In this study, our established heart-specific KO Atp8 ( Atp8 MHC-Cre ) and Nd1 ( Nd1 MHC-Cre ) rats displayed growth retardation, short life span, dilated cardiomyopathy, and impaired mitochondria structure.…”

Section: Discussionmentioning

confidence: 99%

A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon

Tan

Kong

et al. 2023

Sci. Adv.

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Hundreds of pathogenic variants of mitochondrial DNA (mtDNA) have been reported to cause mitochondrial diseases, which still lack effective treatments. It is a huge challenge to install these mutations one by one. We repurposed the DddA-derived cytosine base editor to incorporate a premature stop codon in the mtProtein-coding genes to ablate mitochondrial proteins encoded in the mtDNA (mtProteins) instead of installing pathogenic variants and generated a library of both cell and rat resources with mtProtein depletion. In vitro, we depleted 12 of 13 mtProtein-coding genes with high efficiency and specificity, resulting in decreased mtProtein levels and impaired oxidative phosphorylation. Moreover, we generated six conditional knockout rat strains to ablate mtProteins using Cre/loxP system . Mitochondrially encoded ATP synthase membrane subunit 8 and NADH:ubiquinone oxidoreductase core subunit 1 were specifically depleted in heart cells or neurons, resulting in heart failure or abnormal brain development. Our work provides cell and rat resources for studying the function of mtProtein-coding genes and therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon

Tan

Kong

et al. 2023

Sci. Adv.

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“…Other examples are mitophagy, which is often deregulated in PD, and mutant huntingtin, which is found to be associated with the mitochondrial outer membrane influencing mitochondrial permeability transition pore opening (mPTP). Also, the ALS-related SOD1 mutation (G93A) is associated with mitochondrial respiratory dysfunction and severe mitochondria-induced oxidative stress of proteins and lipids (for a complete review on the mitochondria role in ND, refer to the studies of Jishi and Qi (2022) and Ali et al (2021) .…”

Section: Mitochondria-dependent Protein Aggregation At the Crossroad ...mentioning

confidence: 99%

Mitochondria inter-organelle relationships in cancer protein aggregation

Genovese

Fornetti

Ruocco

2022

Front. Cell Dev. Biol.

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Mitochondria are physically associated with other organelles, such as ER and lysosomes, forming a complex network that is crucial for cell homeostasis regulation. Inter-organelle relationships are finely regulated by both tether systems, which maintain physical proximity, and by signaling cues that induce the exchange of molecular information to regulate metabolism, Ca2+ homeostasis, redox state, nutrient availability, and proteostasis. The coordinated action of the organelles is engaged in the cellular integrated stress response. In any case, pathological conditions alter functional communication and efficient rescue pathway activation, leading to cell distress exacerbation and eventually cell death. Among these detrimental signals, misfolded protein accumulation and aggregation cause major damage to the cells, since defects in protein clearance systems worsen cell toxicity. A cause for protein aggregation is often a defective mitochondrial redox balance, and the ER freshly translated misfolded proteins and/or a deficient lysosome-mediated clearance system. All these features aggravate mitochondrial damage and enhance proteotoxic stress. This review aims to gather the current knowledge about the complex liaison between mitochondria, ER, and lysosomes in facing proteotoxic stress and protein aggregation, highlighting both causes and consequences. Particularly, specific focus will be pointed to cancer, a pathology in which inter-organelle relations in protein aggregation have been poorly investigated.

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“…Mitophagosomes then fuse with lysosomes and lysosomal proteases degrade the mitochondria ( Figure 1D ). Additional mechanistic information on the activation and regulation of mitophagy can be found elsewhere ( Jishi and Qi, 2022 ; Li et al, 2022 ).…”

Section: Functional Overview Of Pten-induced Kinase 1/parkin Dependen...mentioning

confidence: 99%

Defective PTEN-induced kinase 1/Parkin mediated mitophagy and neurodegenerative diseases

Braun

Puglielli²

2022

Front. Cell. Neurosci.

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The selective degradation of mitochondria through mitophagy is a crucial process for maintaining mitochondrial function and cellular health. Mitophagy is a specialized form of selective autophagy that uses unique machinery to recognize and target damaged mitochondria for mitophagosome- and lysosome-dependent degradation. This process is particularly important in cells with high metabolic activity like neurons, and the accumulation of defective mitochondria is a common feature among neurodegenerative disorders. Here, we describe essential steps involved in the induction and progression of mitophagy, and then highlight the various mechanisms that specifically contribute to defective mitophagy in highly prevalent neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis.

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Altered Mitochondrial Protein Homeostasis and Proteinopathies

Cited by 8 publications

References 181 publications

A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon

A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon

Mitochondria inter-organelle relationships in cancer protein aggregation

Defective PTEN-induced kinase 1/Parkin mediated mitophagy and neurodegenerative diseases

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