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Mitochondrial Ca²⁺ Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing.

ABSTRACT: Phagocytes reallocate metabolic resources to kill engulfed pathogens, but the intracellular signals that rapidly switch the immunometabolic program necessary to fuel microbial killing are not understood. We report that macrophages use a fast two-step Ca²⁺ relay to meet the bioenergetic demands of phagosomal killing. Upon detection of a fungal pathogen, macrophages rapidly elevate cytosolic Ca²⁺ (phase 1), and by concurrently activating the mitochondrial Ca²⁺ (mCa²⁺) uniporter (MCU), they trigger a rapid influx of Ca²⁺ into the mitochondria (phase 2). mCa²⁺ signaling reprograms mitochondrial metabolism, at least in part, through the activation of pyruvate dehydrogenase (PDH). Deprived of mCa²⁺ signaling, Mcu^-/- macrophages are deficient in phagosomal reactive oxygen species (ROS) production and defective at killing fungi. Mice lacking MCU in their myeloid cells are highly susceptible to disseminated candidiasis. In essence, this study reveals an elegant design principle that MCU-dependent Ca²⁺ signaling is an electrometabolic switch to fuel phagosome killing.

SUBMITTER: Seegren PV

PROVIDER: S-EPMC7793167 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Mitochondrial Ca2+ Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing.

Seegren Philip V PV Downs Taylor K TK Stremska Marta E ME Harper Logan R LR Cao Ruofan R Olson Rachel J RJ Upchurch Clint M CM Doyle Catherine A CA Kennedy Joel J Stipes Eric L EL Leitinger Norbert N Periasamy Ammasi A Desai Bimal N BN

Cell reports 20201101 8

Phagocytes reallocate metabolic resources to kill engulfed pathogens, but the intracellular signals that rapidly switch the immunometabolic program necessary to fuel microbial killing are not understood. We report that macrophages use a fast two-step Ca2+ relay to meet the bioenergetic demands of phagosomal killing. Upon detection of a fungal pathogen, macrophages rapidly elevate cytosolic Ca2+ (phase 1), and by concurrently activating the mitochondrial Ca2+ (mCa ...[more]

PMID: 33238121

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Project description:Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) increase myofilament Ca2+ sensitivity. Mouse models exhibit increased Ca2+ buffering and arrhythmias, and we hypothesized that these changes are primary effects of the mutations (independent of compensatory changes) and that increased Ca2+ buffering and altered Ca2+ handling contribute to HCM pathogenesis via activation of Ca2+-dependent signaling. Here, we determined the primary effects of HCM mutations on intracellular Ca2+ handling and Ca2+-dependent signaling in a model system possessing Ca2+-handling mechanisms and contractile protein isoforms closely mirroring the human environment in the absence of potentially confounding remodeling. Using adenovirus, we expressed HCM-causing variants of human troponin-T, troponin-I, and α-tropomyosin (R92Q, R145G, and D175N, respectively) in isolated guinea pig left ventricular cardiomyocytes. After 48 h, each variant had localized to the I-band and comprised ∼50% of the total protein. HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes. We observed increased diastolic [Ca2+] and slowed Ca2+ reuptake, coupled with a significant decrease in basal sarcomere length and slowed relaxation. HCM mutant cells had higher sodium/calcium exchanger activity, sarcoplasmic reticulum Ca2+ load, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity driven by Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of phospholamban. The ryanodine receptor (RyR) leak/load relationship was also increased, driven by CaMKII-mediated RyR phosphorylation. Altered Ca2+ homeostasis also increased signaling via both calcineurin/NFAT and extracellular signal-regulated kinase pathways. Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM.

Dataset Information

Mitochondrial Ca²⁺ Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing.

Publications

Mitochondrial Ca<sup>2+</sup> Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing.

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