CaMKIV regulates mitochondrial dynamics during sepsis. (December 2020)

• Record Type: Journal Article
• Authors: Zhang, Xianghong; Griepentrog, John E.; Zou, Baobo; Xu, Li; Cyr, Anthony R.; Chambers, Lauran M.; Zuckerbraun, Brian S.; Shiva, Sruti; Rosengart, Matthew R.
• Is Part Of: Cell calcium. Volume 92(2020)
• Publication Date: 2020-12
• Subjects: Ca2+ calcium -- CaMK Calcium/calmodulin-dependent protein kinase -- CCCP Carbonyl cyanide m-chlorophenyl hydrazine -- CLP cecal ligation and puncture -- DRP1 Dynamin-related protein 1 -- LPS lipopolysaccharide -- Mφ macrophage -- MFN Mitofusin -- MMP (ΔΨ)mitochondrial membrane potential -- OPA1 Mitochondrial dynamin like GTPase -- PINK1 PTEN-induced kinase 1; Calcium -- Mitochondria -- Mitophagy -- Fission -- Fusion; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2020.102286
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: An important role for bioenergetic dysfunction in the development of multiple organ dysfunction has been identified. During sepsis, CaMKIV links mitochondrial stress with adaptive mechanisms of mitochondrial fission, fusion and mitophagy. CaMKIV funtions as a direct PINK1-kinase to induce Parkin-dependent mitophagy and slow oxidative metabolism. CaMKIV shifts the balance away from fusion and towards fission, which correlates with reduced toxic protein oxidation. Abstract: Sepsis and shock states impose mitochondrial stress, and in response, adaptive mechanisms such as fission, fusion and mitophagy are induced to eliminate damaged portions of or entire dysfunctional mitochondria. The mechanisms underlying these events are being elucidated; yet a direct link between loss of mitochondrial membrane potential ΔΨm and the initiation of fission, fusion and mitophagy remains to be well characterized. The direct association between the magnitude of the ΔΨm and the capacity for mitochondria to buffer Ca 2+ renders Ca 2+ uniquely suited as the signal engaging these mechanisms in circumstances of mitochondrial stress that lower the ΔΨm. Herein, we show that the calcium/calmodulin-dependent protein kinase (CaMK) IV mediates an adaptive slowing in oxidative respiration that minimizes oxidative stress in the kidneys of mice subjected to either cecal ligation and puncture (CLP) sepsis or endotoxemia. CaMKIV shifts the balance towards mitochondrial fission and away from fusion by 1) directly phosphorylating an activating Serine616 on the fission protein DRP1 and 2) reducing the expression of the fusion proteins Mfn1/2 and OPA-1. CaMKIV, through its function as a direct PINK1 kinase and regulator of Parkin expression, also enables mitophagy. These data support that CaMKIV serves as a keystone linking mitochondrial stress with the adaptive mechanisms of mitochondrial fission, fusion and mitophagy that mitigate oxidative stress in the kidneys of mice responding to sepsis.