Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform

Zachari, Maria; Guðmundsson, Sigurður; Li, Ziyue; Manifava, Maria; Cugliandolo, Fiorella; Shah, Rohan; Smith, Matthew D.; Stronge, James; Karanasios, Eleftherios; Piunti, Caterina; Kishi‐Itakura, Chieko; Vihinen, Helena; Jokitalo, Eija; Guan, Jun‐Lin; Buß, Folma; Smith, Andrew M.; Walker, Simon; Eskelinen, Eeva‐Liisa; Ktistakis, Nicholas T.

doi:10.1016/j.devcel.2020.10.002

Cited by 11 publications

(12 citation statements)

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“…Moreover, exogenous TRAF2 is sufficient to induce mitophagy in cardiac myocytes ( Figures 7I and 7J ). Indeed, TRAF2 was uncovered in a screen for PINK1 and PARKIN-independent mitophagy mediators, 45 and inflammatory stimuli were observed to induce TRAF2-mediated mitophagy via ubiquitination of orphan nuclear receptor, Nur77, 46 independently confirming our prior observations that TRAF2 mediates mitophagy in cardiac myocytes in culture 26 and in unstressed hearts, in vivo (current dataset). Consistent with a role for PINK1-mediated mitophagy under stress, we found that PINK1 was essential for recruitment of TRAF2 to mitochondrial fraction upon hypoxia-reoxygenation injury, but did not affect TRAF2’s localization to the mitochondria under unstressed normoxic conditions ( Supplemental Figure S2 ).…”

Section: Discussionsupporting

confidence: 87%

TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

Rawnsley

Kovács

et al. 2022

JACC: Basic to Translational Science

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Section: Discussionsupporting

confidence: 87%

TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

Rawnsley

Kovács

et al. 2022

JACC: Basic to Translational Science

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“…This is consistent with the lack of homeostatic mitophagy defects observed in Parkin and PINK1 deficient myocardium in unstressed young adult mice. 8,12,19,20,22 Indeed, TRAF2 was uncovered in a screen for PINK1 and Parkin-independent mitophagy mediators 48 ; and inflammatory stimuli were observed to induce TRAF2-mediated mitophagy via ubiquitination of orphan nuclear receptor, Nur77 32 ; independently confirming our prior observations that TRAF2 mediates mitophagy in cardiac myocytes. 30 Consistent with a role for PINK1-mediated mitophagy under stress, we found that PINK1 was essential for recruitment of TRAF2 to mitochondrial fraction upon hypoxia-reoxygenation injury; but did not affect TRAF2's localization to the mitochondria under unstressed normoxic conditions (Fig.…”

Section: Discussionsupporting

confidence: 78%

TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis

Kovács

et al. 2021

Preprint

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Mitochondrial damage triggers cell death signaling with catastrophic consequences in long-lived and irreplaceable cells, such as cardiac myocytes. Sensing of leaked mitochondrial DNA upon mitochondrial damage is also a potent trigger of inflammation. Whether the innate immune response pathways monitor mitochondrial damage in mitochondria-rich cardiac myocytes to prevent inflammation and cell death, remains unknown. TRAF2, an adaptor protein downstream of innate immune receptors, localizes to the mitochondria in the unstressed heart, with increased mitochondrial targeting in cardiomyopathic human hearts and after cardiac ischemia-reperfusion injury in mice. Inducible cardiomyocyte-specific deletion of TRAF2 in young adult mice impairs mitophagy with rapid decline in mitochondrial quality, upregulates TLR9 expression in cardiac myocytes, and results in inflammation and cell death manifesting as a fulminant cardiomyopathy. Preventing TLR9-mediated mitochondrial DNA sensing and resultant inflammation provides a short-term reprieve from cardiomyopathy, but persistence of damaged mitochondria results in long-term recrudescence. Restoration of TRAF2, but not the E3 ubiquitin ligase deficient mutant improves mitochondrial quality and rescues cardiomyopathy to restore homeostasis. Thus, the innate immune response acts via TRAF2 as the first line of defense against mitochondrial damage by orchestrating homeostatic mitophagy to dampen myocardial inflammation and prevent cell death.

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“…3 g). Mitophagy is selective autophagy that removes defective mitochondria in cells [ 22 ]. Finally, as expected, downregulation of PINK1 induced robust intracellular ROS (DCF-DA, green) and mitochondrial superoxide accumulation (MitoSOX™, red) in cells during osteoblastic differentiation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Pink1 is a core regulator of mitophagy, which is a form of selective macroautophagy of mitochondria [ 22 ]. PINK1 consists of an N-terminal mitochondrial targeting sequence (MTS), an α-helical transmembrane segment, and a serine/threonine kinase domain [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis

Lee

Kim

et al. 2021

Stem Cell Res Ther

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Background PTEN-induced kinase 1 (PINK1) is a serine/threonine-protein kinase in mitochondria that is critical for mitochondrial quality control. PINK1 triggers mitophagy, a selective autophagy of mitochondria, and is involved in mitochondrial regeneration. Although increments of mitochondrial biogenesis and activity are known to be crucial during differentiation, data regarding the specific role of PINK1 in osteogenic maturation and bone remodeling are limited. Methods We adopted an ovariectomy model in female wildtype and Pink1−/− mice. Ovariectomized mice were analyzed using micro-CT, H&E staining, Masson’s trichrome staining. RT-PCR, western blot, immunofluorescence, alkaline phosphatase, and alizarin red staining were performed to assess the expression of PINK1 and osteogenic markers in silencing of PINK1 MC3T3-E1 cells. Clinical relevance of PINK1 expression levels was determined via qRT-PCR analysis in normal and osteoporosis patients. Results A significant decrease in bone mass and collagen deposition was observed in the femurs of Pink1−/− mice after ovariectomy. Ex vivo, differentiation of osteoblasts was inhibited upon Pink1 downregulation, accompanied by impaired mitochondrial homeostasis, increased mitochondrial reactive oxygen species production, and defects in mitochondrial calcium handling. Furthermore, PINK1 expression was reduced in bones from patients with osteoporosis, which supports the practical role of PINK1 in human bone disease. Conclusions In this study, we demonstrated that activation of PINK1 is a requisite in osteoblasts during differentiation, which is related to mitochondrial quality control and low reactive oxygen species production. Enhancing PINK1 activity might be a possible treatment target in bone diseases as it can promote a healthy pool of functional mitochondria in osteoblasts.

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Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform

Cited by 11 publications

References 0 publications

TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis

PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis

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