Mitochondrial proteotoxicity: implications and ubiquitin-dependent quality control mechanisms

Karbowski, Mariusz; Oshima, Yumiko; Verhoeven, Nicolas

doi:10.1007/s00018-022-04604-8

Cited by 6 publications

(5 citation statements)

References 228 publications

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“…Previous evidence has indicated that DRP1 can be activated in different ways to drive mitochondria division in mammals 34 , 56 . It stands to reason that the role of DRP1 in this model of mitophagy may participate in providing mitochondrial fragments small enough to be cleared by autophagy 57 , but the detailed mechanism needs to be further investigated. Additionally, a preceding study has demonstrated that the autophagy adapter SQSTM1 recruits two CRL subunits Keap1 and Rbx1 to the mitochondria and then promotes OMM ubiquitination 58 .…”

Section: Discussionmentioning

confidence: 99%

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: 99%

Burkholderia pseudomallei BipD modulates host mitophagy to evade killing

Nan,

Rao,

Tang

et al. 2024

Nat Commun

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“…Mitochondrial dysfunction is key for neurodegenerative diseases [ 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. Mitochondria are at the core of cellular energy production and interruption of the crosstalk between cell signaling and mitochondrial functions and biogenesis, and result in mitochondrial dysfunction, proteotoxic stress, accumulation of defective mitochondria, and the production of reactive oxygen species due to defective mitophagy and major alterations in the ubiquitin–proteasome system [ 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 ,…”

Section: Apoe4 Brain Effectsmentioning

confidence: 99%

“…The ubiquitin–proteasome system is a crucial player in protein surveillance on the mitochondrial surface [ 102 ]. Proteotoxic stress, defined in Karbowski et al [ 103 ] as a reduction in bioenergetic activity induced by the accumulation of aberrant proteins in the mitochondria, is a mechanism at play in several neurodegenerative diseases. Mitochondrial unfolded protein responses (mtUPR), the ubiquitin (Ub)-dependent degradation of aberrant mitochondrial proteins, and mitochondria-specific autophagy (mitophagy) all respond to proteotoxic stress and eliminate defective proteins or dysfunctional mitochondria.…”

Section: Apoe4 Brain Effectsmentioning

confidence: 99%

APOE Peripheral and Brain Impact: APOE4 Carriers Accelerate Their Alzheimer Continuum and Have a High Risk of Suicide in PM2.5 Polluted Cities

Calderón‐Garcidueñas

Hernández-Luna²,

Aiello-Mora

et al. 2023

Biomolecules

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This Review emphasizes the impact of APOE4—the most significant genetic risk factor for Alzheimer’s disease (AD)—on peripheral and neural effects starting in childhood. We discuss major mechanistic players associated with the APOE alleles’ effects in humans to understand their impact from conception through all life stages and the importance of detrimental, synergistic environmental exposures. APOE4 influences AD pathogenesis, and exposure to fine particulate matter (PM2.5), manufactured nanoparticles (NPs), and ultrafine particles (UFPs) associated with combustion and friction processes appear to be major contributors to cerebrovascular dysfunction, neuroinflammation, and oxidative stress. In the context of outdoor and indoor PM pollution burden—as well as Fe, Ti, and Al alloys; Hg, Cu, Ca, Sn, and Si UFPs/NPs—in placenta and fetal brain tissues, urban APOE3 and APOE4 carriers are developing AD biological disease hallmarks (hyperphosphorylated-tau (P-tau) and amyloid beta 42 plaques (Aβ42)). Strikingly, for Metropolitan Mexico City (MMC) young residents ≤ 40 y, APOE4 carriers have 4.92 times higher suicide odds and 23.6 times higher odds of reaching Braak NFT V stage versus APOE4 non-carriers. The National Institute on Aging and Alzheimer’s Association (NIA-AA) framework could serve to test the hypothesis that UFPs and NPs are key players for oxidative stress, neuroinflammation, protein aggregation and misfolding, faulty complex protein quality control, and early damage to cell membranes and organelles of neural and vascular cells. Noninvasive biomarkers indicative of the P-tau and Aβ42 abnormal protein deposits are needed across the disease continuum starting in childhood. Among the 21.8 million MMC residents, we have potentially 4 million APOE4 carriers at accelerated AD progression. These APOE4 individuals are prime candidates for early neuroprotective interventional trials. APOE4 is key in the development of AD evolving from childhood in highly polluted urban centers dominated by anthropogenic and industrial sources of pollution. APOE4 subjects are at higher early risk of AD development, and neuroprotection ought to be implemented. Effective reductions of PM2.5, UFP, and NP emissions from all sources are urgently needed. Alzheimer’s Disease prevention ought to be at the core of the public health response and physicians-scientist minority research be supported.

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“…Alteration in any of these pathways compromises mitochondrial quality and may potentially lead to impaired muscle function. Another important mechanism involved in MQC is the mitochondrial unfolded protein response (UPR mt ), which plays a pivotal role in maintaining mitochondrial proteostasis [29].…”

Section: Introductionmentioning

confidence: 99%

Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle

Senese,

Petito,

Silvestri

et al. 2024

Biology

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This study aims to explore the complex role of cannabinoid type 1 receptor (CB1) signaling in the gastrocnemius muscle, assessing physiological processes in both CB1+/+ and CB1−/− mice. The primary focus is to enhance our understanding of how CB1 contributes to mitochondrial homeostasis. At the tissue level, CB1−/− mice exhibit a substantial miRNA-related alteration in muscle fiber composition, characterized by an enrichment of oxidative fibers. CB1 absence induces a significant increase in the oxidative capacity of muscle, supported by elevated in-gel activity of Complex I and Complex IV of the mitochondrial respiratory chain. The increased oxidative capacity is associated with elevated oxidative stress and impaired antioxidant defense systems. Analysis of mitochondrial biogenesis markers indicates an enhanced capacity for new mitochondria production in CB1−/− mice, possibly adapting to altered muscle fiber composition. Changes in mitochondrial dynamics, mitophagy response, and unfolded protein response (UPR) pathways reveal a dynamic interplay in response to CB1 absence. The interconnected mitochondrial network, influenced by increased fusion and mitochondrial UPR components, underlines the dual role of CB1 in regulating both protein quality control and the generation of new mitochondria. These findings deepen our comprehension of the CB1 impact on muscle physiology, oxidative stress, and MQC processes, highlighting cellular adaptability to CB1−/−. This study paves the way for further exploration of intricate signaling cascades and cross-talk between cellular compartments in the context of CB1 and mitochondrial homeostasis.

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Mitochondrial proteotoxicity: implications and ubiquitin-dependent quality control mechanisms

Cited by 6 publications

References 228 publications

Burkholderia pseudomallei BipD modulates host mitophagy to evade killing

Burkholderia pseudomallei BipD modulates host mitophagy to evade killing

APOE Peripheral and Brain Impact: APOE4 Carriers Accelerate Their Alzheimer Continuum and Have a High Risk of Suicide in PM2.5 Polluted Cities

Effect of CB1 Receptor Deficiency on Mitochondrial Quality Control Pathways in Gastrocnemius Muscle

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