Allen 2020 Commun Biol
|Allen ME, Pennington ER, Perry JB, Dadoo S, Makrecka-Kuka M, Dambrova M, Moukdar F, Patel HD, Han X, Kidd GK, Benson EK, Raisch TB, Poelzing S, Brown DA, Shaikh SR (2020) The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats. Commun Biol 3:389.|
Allen Mitchell E, Pennington Edward Ross, Perry Justin B, Dadoo Sahil, Makrecka-Kuka Marina, Dambrova Maija, Moukdar Fatiha, Patel Hetal D, Han Xianlin, Kidd Grahame K, Benson Emily K, Raisch Tristan B, Poelzing Steven, Brown David A, Shaikh Saame Raza (2020) Commun Biol
Abstract: Mitochondrial dysfunction contributes to cardiac pathologies. Barriers to new therapies include an incomplete understanding of underlying molecular culprits and a lack of effective mitochondria-targeted medicines. Here, we test the hypothesis that the cardiolipin-binding peptide elamipretide, a clinical-stage compound under investigation for diseases of mitochondrial dysfunction, mitigates impairments in mitochondrial structure-function observed after rat cardiac ischemia-reperfusion. Respirometry with permeabilized ventricular fibers indicates that ischemia-reperfusion induced decrements in the activity of complexes I, II, and IV are alleviated with elamipretide. Serial block face scanning electron microscopy used to create 3D reconstructions of cristae ultrastructure reveals that disease-induced fragmentation of cristae networks are improved with elamipretide. Mass spectrometry shows elamipretide did not protect against the reduction of cardiolipin concentration after ischemia-reperfusion. Finally, elamipretide improves biophysical properties of biomimetic membranes by aggregating cardiolipin. The data suggest mitochondrial structure-function are interdependent and demonstrate elamipretide targets mitochondrial membranes to sustain cristae networks and improve bioenergetic function.
Labels: MiParea: Respiration, Pharmacology;toxicology
Stress:Ischemia-reperfusion Organism: Rat Tissue;cell: Heart Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET Pathway: N, S, CIV HRR: Oxygraph-2k