PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?

Silvian, Laura

doi:10.3389/fnagi.2022.890823

Cited by 23 publications

(12 citation statements)

References 37 publications

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“…Under physiological conditions, PINK1 is transported to the inner mitochondrial membrane (IMM) and degraded by presenilin‐associated rhomboid‐like protease (PARL) 53 . However, in damaged mitochondria, the degradation of PINK1 is inhibited to maintain PINK1 present on the outer mitochondrial membrane (OMM) 54 . PINK1 accumulation on the OMM further mediates the phosphorylation of ubiquitin (Ub) at Ser65 and the phosphorylation of Ser65 in the ubiquitin‐like (UBL) domain of Parkin 55,56 .…”

Section: Discussionmentioning

confidence: 99%

Human umbilical cord mesenchymal stem cell‐derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin‐mediated mitophagy

et al. 2023

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Aims: Recently, human umbilical cord mesenchymal stem cell (HucMSC)-derived exosome is a new focus of research in neurological diseases. The present study was aimed to investigate the protective effects of HucMSC-derived exosome in both in vivo and in vitro TBI models. Methods:We established both mouse and neuron TBI models in our study. After treatment with HucMSC-derived exosome, the neuroprotection of exosome was investigated by the neurologic severity score (NSS), grip test score, neurological score, brain water content, and cortical lesion volume. Moreover, we determined the biochemical and morphological changes associated with apoptosis, pyroptosis, and ferroptosis after TBI. Results:We revealed that treatment of exosome could improve neurological function, decrease cerebral edema, and attenuate brain lesion after TBI. Furthermore, administration of exosome suppressed TBI-induced cell death, apoptosis, pyroptosis, and ferroptosis. In addition, exosome-activated phosphatase and tensin homolog-induced putative kinase protein 1/Parkinson protein 2 E3 ubiquitin-protein ligase (PINK1/ Parkin) pathway-mediated mitophagy after TBI. However, the neuroprotection of exosome was attenuated when mitophagy was inhibited, and PINK1 was knockdown.Importantly, exosome treatment also decreased neuron cell death, suppressed apoptosis, pyroptosis, and ferroptosis and activated the PINK1/Parkin pathway-mediated mitophagy after TBI in vitro. Conclusion:Our results provided the first evidence that exosome treatment played a key role in neuroprotection after TBI through the PINK1/Parkin pathway-mediated mitophagy.

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Section: Discussionmentioning

confidence: 99%

Human umbilical cord mesenchymal stem cell‐derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin‐mediated mitophagy

et al. 2023

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“…This process is highly controlled by deubiqutinases, including USP30 62 . For that reason, upregulation of PINK1-Parkin or inhibition of USP30 have been pursued as a potential therapeutics for PD 63 . Interestingly, we find downregulation of PINK1 and increase in USP30 and other deubiqutinases (USP38, USP42) in LAMDA, suggesting the validity of this therapeutic approach for idiopathic PD.…”

Section: Discussionmentioning

confidence: 99%

Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology

Goralski,

Meyerdirk,

Breton

et al. 2023

Preprint

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Lewy pathology composed of α-synuclein is the key pathological hallmark of Parkinson’s disease (PD), found both in dopaminergic neurons that control motor function, and throughout cortical regions that control cognitive function. Recent work has investigated which dopaminergic neurons are most susceptible to death, but little is known about which neurons are vulnerable to developing Lewy pathology and what molecular changes an aggregate induces. In the current study, we use spatial transcriptomics to selectively capture whole transcriptome signatures from cortical neurons with Lewy pathology compared to those without pathology in the same brains. We find, both in PD and in a mouse model of PD, that there are specific classes of excitatory neurons that are vulnerable to developing Lewy pathology in the cortex. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. This gene signature indicates that neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. However, beyond DNA repair gene upregulation, we find that neurons also activate apoptotic pathways, suggesting that if DNA repair fails, neurons undergo programmed cell death. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and identify a conserved signature of molecular dysfunction in both mice and humans.

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“…Hyperglycemia causes mitochondrial damage, and damaged or dysfunctional mitochondria are constantly cleared by mitophagy [22][23][24][25][26]. The removal of damaged mitochondria is a fundamental process in the mitochondrial quality control mechanism, and retaining healthy mitochondria via mitochondrial quality control mechanisms is accomplished via several mitophagy marker proteins [27,28,10]. FUNDC1 is not only a mitophagy receptor, but it also regulates angiogenesis and neoangiogenesis [9].…”

Section: Discussionmentioning

confidence: 99%

BAM15, a mitochondrial uncoupler regulates mitochondrial function by FUNDC1 dependently in hyperglycemia

Rethineswaran,

Jang,

Choi

et al. 2023

Preprint

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Mitochondria are intracellular organelles that regulate cell survival and death, and hyperglycemia modulates mitochondrial function in endothelial cells. In the current study, we have discovered that high glucose (HG) treatment reduces FUNDC1 (FUN14 domain containing 1) expression in endothelial cells. FUNDC1 expression in mitochondria inhibits proteasomal degradation of COX-IV, and regulates mitochondrial complexes I and IV activity and ATP synthesis. FUNDC1 depletion in HG affects mitochondrial complexes I and IV activity and ATP synthesis and promotes mitochondrial damage through loss of mitochondrial membrane potential and ROS (Reactive Oxygen Species) production. BAM15, a mitochondrial uncoupler, improves mitochondrial function and endothelial survival more effectively. Co-treatment of HG with BAM15 increased FUNDC1 protein expression, mitochondrial translocation of FUNDC1 in HG-treated cells. BAM15-induced up regulation of FUNDC1 expressions improve mitochondrial expression of COX-IV, and complex I and IV activity and ATP synthesis. Our findings propose that FUNDC1 expression in endothelial cells under hyperglycemic stress play a significant role in limiting vascular damage and apoptotic cell death.

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PINK1/Parkin Pathway Activation for Mitochondrial Quality Control – Which Is the Best Molecular Target for Therapy?

Cited by 23 publications

References 37 publications

Human umbilical cord mesenchymal stem cell‐derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin‐mediated mitophagy

Human umbilical cord mesenchymal stem cell‐derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin‐mediated mitophagy

Spatial transcriptomics reveals molecular dysfunction associated with Lewy pathology

BAM15, a mitochondrial uncoupler regulates mitochondrial function by FUNDC1 dependently in hyperglycemia

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