Akap1 Deficiency Promotes Mitochondrial Aberrations and Exacerbates Cardiac Injury Following Permanent Coronary Ligation via Enhanced Mitophagy and Apoptosis

Schiattarella, Gabriele Giacomo; Cattaneo, Fabio; Pironti, Gianluigi; Magliulo, Fabio; Colella, Giuseppe; Pirozzi, Marinella; Polishchuk, Roman; Borzacchiello, Domenica; Paolillo, Roberta; Oliveti, Marco; Boccella, Nicola; Avvedimento, Marisa; Sepe, Maria; Lombardi, Assunta; Busiello, Rosa Anna; Trimarco, Bruno; Esposito, Giovanni; Feliciello, Antonio; Perrino, Cinzia

doi:10.1371/journal.pone.0154076

Cited by 43 publications

(53 citation statements)

References 35 publications

(46 reference statements)

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“…In the current study, our findings showed that loss of AKAP1 increased LC3-II protein expression but decreased p62 protein expression in AKAP1 −/− retina. Intriguingly, AKAP1 −/− heart reduced p62 protein expression and enhanced mitophagy and apoptosis 46 . Collectively, our results suggest that the increased LC3-II and decreased p62 contribute to the induction of autophagy/mitophagy in AKAP1 −/− retina.…”

Section: Discussionmentioning

confidence: 97%

“…These results suggest that AKAP1 loss induces an imbalance of mitochondrial dynamics by triggering mitochondrial fission and loss in RGCs. AKAP1 loss promotes mitochondrial abnormalities and mitophagy in cardiac injury 46 . Based on our current findings of mitochondrial fission and loss, we determined whether AKAP1 loss induces mitophagosome formation.…”

Section: Akap1 Loss Causes Mitochondrial Fission and Mitophagosome Fomentioning

confidence: 99%

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Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

et al. 2020

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Impairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases in CaN and total Drp1 levels, as well as a decrease in Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.

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Section: Discussionmentioning

confidence: 97%

Section: Akap1 Loss Causes Mitochondrial Fission and Mitophagosome Fomentioning

confidence: 99%

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

et al. 2020

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“…Single nucleotide polymorphisms in Akap1 can alter the subcellular distribution of AKAP1 variants and alter the outcomes of cAMP/PKA signaling . Indeed, the relative levels of AKAP1 on the mitochondria can influence the outcomes of local PKA signaling . By merely increasing AKAP‐1 concentrations on mitochondria, investigators have been able to leverage the prominent concentrations of PKA in the cytosol to influence mitochondrial health.…”

Section: Omm Scaffold Proteinsmentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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“…AKAP1 loss promotes mitochondrial abnormalities and mitophagy in cardiac injury 53 . Based on our current findings of mitochondrial fission and loss, we determined whether AKAP1 loss induces mitophagosome formation using Western blot, immunohistochemistry and EM tomography analyses.…”

Section: Akap1 Loss Causes Mitochondrial Fission and Mitophagosome Fomentioning

confidence: 99%

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

Edwards

Perkins

Kim

et al. 2019

Preprint

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AbstractImpairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases of CaN and total Drp1 level, as well as a decrease of Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.

show abstract

Akap1 Deficiency Promotes Mitochondrial Aberrations and Exacerbates Cardiac Injury Following Permanent Coronary Ligation via Enhanced Mitophagy and Apoptosis

Cited by 43 publications

References 35 publications

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells

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