SAMM50 acts with p62 in piecemeal basal- and OXPHOS-induced mitophagy of SAM and MICOS components

Abudu, Yakubu Princely; Shrestha, Birendra Kumar; Zhang, Wenxin; Palara, Anthimi; Brenne, Hanne Britt; Larsen, Kenneth Bowitz; Wolfson, Deanna L.; Dumitriu, Gianina; Øie, Cristina Ionica; Ahluwalia, Balpreet Singh; Levy, Gahl; Behrends, Christian; Tooze, Sharon A.; Mouilleron, S.; Lamark, Trond; Johansen, Terje

doi:10.1083/jcb.202009092

“…Further understanding the mechanism by which Samm50 regulates mitophagy in cardiac hypertrophy is important for exploring the new strategies for treatment. Samm50 is a critical regulator of Pink1-Parkin-mediated or P62-mediated mitophagy ( 25 , 34 ), whereas most mitophagy signals converge on the Pink1-Parkin-mediated pathway. Fenglei et al revealed that Samm50 interacts with Pink1 and regulates its stability in HeLa cells ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes

Xu

¹

,

Kang

²

,

Wei

³

et al. 2021

Front. Cardiovasc. Med.

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Pathological cardiac hypertrophy, the adaptive response of the myocardium to various pathological stimuli, is one of the primary predictors and predisposing factors of heart failure. However, its molecular mechanisms underlying pathogenesis remain poorly understood. Here, we studied the function of Samm50 in mitophagy during Ang II-induced cardiomyocyte hypertrophy via lentiviruses mediated knockdown and overexpression of Samm50 protein. We first found that Samm50 is a key positive regulator of cardiac hypertrophy, for western blot and real-time quantitative PCR detection revealed Samm50 was downregulated both in pressure-overload-induced hypertrophic hearts and Ang II-induced cardiomyocyte hypertrophy. Then, Samm50 overexpression exhibits enhanced induction of cardiac hypertrophy marker genes and cell enlargement in primary mouse cardiomyocytes by qPCR and immunofluorescence analysis, respectively. Meanwhile, Samm50 remarkably reduced Ang II-induced autophagy as indicated by decreased mitophagy protein levels and autophagic flux, whereas the opposite phenotype was observed in Samm50 knockdown cardiomyocytes. However, the protective role of Samm50 deficiency against cardiac hypertrophy was abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown. Moreover, we further demonstrated that Samm50 interacted with Pink1 and stimulated the accumulation of Parkin on mitochondria to initiate mitophagy by co-immunoprecipitation analysis and immunofluorescence. Thus, these results suggest that Samm50 regulates Pink1-Parkin-mediated mitophagy to promote cardiac hypertrophy, and targeting mitophagy may provide new insights into the treatment of cardiac hypertrophy.

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“…Hence, SAMM50 works as a platform where mitochondrial fission, membrane architecture, and mitophagy components orchestrate membrane protrusions and facilitate VPS35 recruitment. Very recently, SAMM50 has been linked also to piecemeal mitophagy, independent of MDVs, through direct interaction with the p62 adaptor 54 . Hence, we conclude that specific mtDNA degradation does not follow the MDV pathway, despite the fact that they share some components, and that it is more likely that mitochondrial protrusions containing nucleoids are engulfed in autophagosomes in a specialized mitophagy pathway.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA

Pla‐Martín

¹

,

Sen

²

,

Kallabis

³

et al. 2021

Preprint

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Integrity of mitochondrial DNA (mtDNA), encoding several subunits of the respiratory chain, is essential to maintain mitochondrial fitness. Mitochondria, as a central hub for metabolism, are affected in a wide variety of human diseases but also during normal ageing, where mtDNA integrity is compromised. Mitochondrial quality control mechanisms work at different levels, and mitophagy and its variants are critical to remove dysfunctional mitochondria together with mtDNA to maintain cellular homeostasis. Understanding the mechanisms governing a selective turnover of mutation-bearing mtDNA without affecting the entire mitochondrial pool is fundamental to design therapeutic strategies against mtDNA diseases and ageing. Here we show that mtDNA depletion after expressing a dominant negative version of the mitochondrial helicase Twinkle, or by chemical means, is due to an exacerbated mtDNA turnover. Targeting of nucleoids is controlled by Twinkle which, together with the mitochondrial transmembrane proteins ATAD3 and SAMM50, orchestrate mitochondrial membrane remodeling to form extrusions. mtDNA removal depends on autophagy and requires the vesicular trafficking protein VPS35 which binds to Twinkle-enriched mitochondrial subcompartments upon mtDNA damage. Stimulation of autophagy by rapamycin selectively removes mtDNA deletions which accumulated during muscle regeneration in vivo, but without affecting mtDNA copy number. With these results we unveil a new complex mechanism specifically targeting and removing mutant mtDNA which occurs outside the mitochondrial network. We reveal the molecular targets involved in a process with multiple potential benefits against human mtDNA related diseases, either inherited, acquired or due to normal ageing.

show abstract

“…Very recently, SAMM50 has been linked also to piecemeal mitophagy, independent of MDVs, through direct interaction with the p62 adaptor 54 . Hence, we conclude that specific mtDNA degradation does not follow the MDV pathway, despite the fact that they share some components, and that it is more likely that mitochondrial protrusions containing nucleoids are engulfed in autophagosomes in a specialized mitophagy pathway.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.

Pla‐Martín

¹

,

Sen

²

,

Kallabis

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

Integrity of mitochondrial DNA (mtDNA), encoding several subunits of the respiratory chain, is essential to maintain mitochondrial fitness. Mitochondria, as a central hub for metabolism, are affected in a wide variety of human diseases but also during normal ageing, where mtDNA integrity is compromised. Mitochondrial quality control mechanisms work at different levels, and mitophagy and its variants are critical to remove dysfunctional mitochondria together with mtDNA to maintain cellular homeostasis. Understanding the mechanisms governing a selective turnover of mutation-bearing mtDNA without affecting the entire mitochondrial pool is fundamental to design therapeutic strategies against mtDNA diseases and ageing. Here we show that mtDNA depletion after expressing a dominant negative version of the mitochondrial helicase Twinkle, or by chemical means, is due to an exacerbated mtDNA turnover. Targeting of nucleoids is controlled by Twinkle which, together with the mitochondrial transmembrane proteins ATAD3 and SAMM50, orchestrate mitochondrial membrane remodeling to form extrusions. mtDNA removal depends on autophagy and requires the vesicular trafficking protein VPS35 which binds to Twinkle-enriched mitochondrial subcompartments upon mtDNA damage. Stimulation of autophagy by rapamycin selectively removes mtDNA deletions which accumulated during muscle regeneration in vivo, but without affecting mtDNA copy number. With these results we unveil a new complex mechanism specifically targeting and removing mutant mtDNA which occurs outside the mitochondrial network. We reveal the molecular targets involved in a process with multiple potential benefits against human mtDNA related diseases, either inherited, acquired or due to normal ageing.

show abstract

SAMM50 acts with p62 in piecemeal basal- and OXPHOS-induced mitophagy of SAM and MICOS components

Cited by 46 publications

References 114 publications

Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes

Samm50 Promotes Hypertrophy by Regulating Pink1-Dependent Mitophagy Signaling in Neonatal Cardiomyocytes

Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA

Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.

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