Platelet Mitochondria Transplantation Rescues Hypoxia/Reoxygenation-Induced Mitochondrial Dysfunction and Neuronal Cell Death Involving the FUNDC2/PIP3/Akt/FOXO3a Axis

Abstract

Mitochondrial transplantation emerges as a novel therapeutic solution for ischemia/reperfusion injury (IRI) in various tissues. Platelets have recently been used in mitochondrial transplantation as readily-available donors of small-size platelet mitochondria (plt-mito). Interestingly, FUN14 Domain Containing 2 (FUNDC2), a protein highly-expressed in the outer membrane (OMM) of plt-mito, has been identified to maintain platelet survival under hypoxic condition. The current study determined whether and how FUNDC2 contributed to the therapeutic effect of plt-mito transplantation for hypoxia/reoxygenation (HR) injury. The results showed that incorporation of human plt-mito into SH-SY5Y cells rescued HR-induced mitochondrial malfunction and mitochondrial apoptotic pathway. Mechanistically, plt-mito transplantation led to an increased expression of FUNDC2 in the recipient cells. This protein induced mitochondrial translocation of phosphatidylinositol-3,4,5-trisphosphate (PIP3) via its N-term, resulting in the stimulation of the protein kinase B (Akt)/forkhead box O3a (FOXO3a) pathway, which inhibited HR-induced mitochondrial accumulation of a mitochondrial target of FOXO3a, Bim, also known as a pro-apoptotic protein. Therefore, the FUNDC2/PIP3/Akt/FOXO3a axis may facilitate the incorporated plt-mito to restore mitochondrial function and cell viability of the recipient cells, and platelets may serve as readily-available sources of donor mitochondria that afford therapeutic benefits against IRI.

High Dose of Metformin Decreases Susceptibility to Occlusive Arterial Thrombosis Uniquely in Type-2 Diabetic Mice

“…Therefore, we decided to measured platelet mitochondrial bioenergetics in our model. We observed that T2D mice show greater platelet mitochondrial respiration, which is consistent with hyperglycemia-induced increase in glucose metabolism [24] . However, there were no differences with Metformin treatment in any of the parameters we interrogated in T2D treated mice compared to controls (Fig5).…”

High Dose of Metformin Decreases Susceptibility to Occlusive Arterial Thrombosis in Type-2 Diabetic Mice

“…5). T2D mice show higher baseline platelet mitochondrial respiration (23), consistent with hyperglycemia-induced increase in glucose metabolism (24). There were no differences with Metformin treatment in any of the parameters we interrogated in T2D treated mice compared to controls (Fig.…”

EFECTO DE CAMPOS ELECTROMAGNÉTICOS PULSANTES DE 120 HERTZ Y CAMPOS MAGNÉTICOS ESTÁTICOS, SOBRE PARÁMETROS SANGUÍNEOS ENZIMÁTICOS DE RATAS (Rattus norvegicus) LÍNEA SPRAGUE DAWLEY

“…Certos estudos indicam que tais benefícios ocorrem através da reparação da maquinaria bioenergética, possivelmente se fusionando com mitocôndrias hospedeiras (COWAN et al, 2016;XIE et al, 2021). Outros estudos, observando sua localização perinuclear e as baixas taxas de internalização, sugerem que os benefícios atribuídos às mitocôndrias exógenas se encontram na alteração de mecanismos de sinalização e expressão gênica (ALEXANDER et al, 2021;SHI;LIU, 2021). O mais provável é que os efeitos terapêuticos observados sejam resultado da combinação de diversos mecanismos.…”

“…Já mitocôndrias provenientes de músculo esquelético ou cardíaco costumam apresentar semelhantes taxas de internalização(WEIXLER et al, 2020). Alguns trabalhos reportaram baixas taxas de internalização de mitocôndrias exógenas, com variações de eficácias de 3-15%(MA et al, 2020;SHI;LIU, 2021), 15-30% (KITANI et al, 2014HUANG et al, 2016) e 50%(ROBICSEK et al, 2018). Um fator que pode aumentar a taxa de internalização é o estresse celular das células receptoras(BABENKO et al, 2018SUN et al, 2019.…”