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Brain activity regulates loose coupling between mitochondrial and cytosolic Ca²⁺ transients.

ABSTRACT: Mitochondrial calcium ([Ca²⁺]_mito) dynamics plays vital roles in regulating fundamental cellular and organellar functions including bioenergetics. However, neuronal [Ca²⁺]_mito dynamics in vivo and its regulation by brain activity are largely unknown. By performing two-photon Ca²⁺ imaging in the primary motor (M1) and visual cortexes (V1) of awake behaving mice, we find that discrete [Ca²⁺]_mito transients occur synchronously over somatic and dendritic mitochondrial network, and couple with cytosolic calcium ([Ca²⁺]_cyto) transients in a probabilistic, rather than deterministic manner. The amplitude, duration, and frequency of [Ca²⁺]_cyto transients constitute important determinants of the coupling, and the coupling fidelity is greatly increased during treadmill running (in M1 neurons) and visual stimulation (in V1 neurons). Moreover, Ca²⁺/calmodulin kinase II is mechanistically involved in modulating the dynamic coupling process. Thus, activity-dependent dynamic [Ca²⁺]_mito-to-[Ca²⁺]_cyto coupling affords an important mechanism whereby [Ca²⁺]_mito decodes brain activity for the regulation of mitochondrial bioenergetics to meet fluctuating neuronal energy demands as well as for neuronal information processing.

SUBMITTER: Lin Y

PROVIDER: S-EPMC6872662 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Brain activity regulates loose coupling between mitochondrial and cytosolic Ca2+ transients.

Lin Yuan Y Li Lin-Lin LL Nie Wei W Liu Xiaolei X Adler Avital A Xiao Chi C Lu Fujian F Wang Liping L Han Hua H Wang Xianhua X Gan Wen-Biao WB Cheng Heping H

Nature communications 20191121 1

Mitochondrial calcium ([Ca2+]mito) dynamics plays vital roles in regulating fundamental cellular and organellar functions including bioenergetics. However, neuronal [Ca2+]mito dynamics in vivo and its regulation by brain activity are largely unknown. By performing two-photon Ca2+ imaging in the primary motor (M1) and visual cortexes (V1) of awake behaving mice, we find that discrete [Ca2+]mito transients occur synchrono ...[more]

PMID: 31754099

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Project description:Mechanical forces from non-ablative pulsed focused ultrasound (pFUS) generate pro-inflammatory tumor microenvironments (TME), marked by increased cytokines, chemokines, and trophic factors, as well as immune cell infiltration and reduced tumor growth. pFUS also causes DNA damage within tumors, which is a potent activator of immunity and could contribute to changes in the TME. This study investigated mechanisms behind the mechanotransductive effects of pFUS causing DNA damage in several tumor cell types. Methods: 4T1 (murine breast tumor), B16 (murine melanoma), C6 (rat glioma), or MDA-MB-231 (human breast tumor) cells were sonicated in vitro (1.1MHz; 6MPa PNP; 10ms pulses; 10% duty cycle; 300 pulses). DNA damage was detected by TUNEL, apoptosis was measured by immunocytochemistry for cleaved caspase-3. Calcium, superoxide, and H2O2 were detected by fluorescent indicators and modulated by BAPTA-AM, mtTEMPOL, or Trolox, respectively. Results: pFUS increased TUNEL reactivity (range = 1.6-2.7-fold) in all cell types except C6 and did not induce apoptosis in any cell line. All lines displayed cytosolic Ca2+ transients during sonication. pFUS increased superoxide (range = 1.6-2.0-fold) and H2O2 (range = 2.3-2.8-fold) in all cell types except C6. BAPTA-AM blocked increased TUNEL reactivity, superoxide and H2O2 formation, while Trolox also blocked increased TUNEL reactivity increased after pFUS. mtTEMPOL allowed H2O2 formation and did not block increased TUNEL reactivity after pFUS. Unsonicated C6 cells had higher baseline concentrations of cytosolic Ca2+, superoxide, and H2O2, which were not associated with greater baseline TUNEL reactivity than the other cell lines. Conclusions: Mechanotransduction of pFUS directly induces DNA damage in tumor cells by cytosolic Ca2+ transients causing formation of superoxide and subsequently, H2O2. These results further suggest potential clinical utility for pFUS. However, the lack of pFUS-induced DNA damage in C6 cells demonstrates a range of potential tumor responses that may arise from physiological differences such as Ca2+ or redox homeostasis.

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Brain activity regulates loose coupling between mitochondrial and cytosolic Ca²⁺ transients.

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Brain activity regulates loose coupling between mitochondrial and cytosolic Ca<sup>2+</sup> transients.

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