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Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity.

ABSTRACT: Mitochondrial fusion is thought to be important for supporting cardiac contractility, but is hardly detectable in cultured cardiomyocytes and is difficult to directly evaluate in the heart. We overcame this obstacle through in vivo adenoviral transduction with matrix-targeted photoactivatable GFP and confocal microscopy. Imaging in whole rat hearts indicated mitochondrial network formation and fusion activity in ventricular cardiomyocytes. Promptly after isolation, cardiomyocytes showed extensive mitochondrial connectivity and fusion, which decayed in culture (at 24-48 h). Fusion manifested both as rapid content mixing events between adjacent organelles and slower events between both neighboring and distant mitochondria. Loss of fusion in culture likely results from the decline in calcium oscillations/contractile activity and mitofusin 1 (Mfn1), because (i) verapamil suppressed both contraction and mitochondrial fusion, (ii) after spontaneous contraction or short-term field stimulation fusion activity increased in cardiomyocytes, and (iii) ryanodine receptor-2-mediated calcium oscillations increased fusion activity in HEK293 cells and complementing changes occurred in Mfn1. Weakened cardiac contractility in vivo in alcoholic animals is also associated with depressed mitochondrial fusion. Thus, attenuated mitochondrial fusion might contribute to the pathogenesis of cardiomyopathy.

SUBMITTER: Eisner V

PROVIDER: S-EPMC5293028 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity.

Eisner Verónica V Cupo Ryan R RR Gao Erhe E Csordás György G Slovinsky William S WS Paillard Melanie M Cheng Lan L Ibetti Jessica J Chen S R Wayne SR Chuprun J Kurt JK Hoek Jan B JB Koch Walter J WJ Hajnóczky György G

Proceedings of the National Academy of Sciences of the United States of America 20170117 5

Mitochondrial fusion is thought to be important for supporting cardiac contractility, but is hardly detectable in cultured cardiomyocytes and is difficult to directly evaluate in the heart. We overcame this obstacle through in vivo adenoviral transduction with matrix-targeted photoactivatable GFP and confocal microscopy. Imaging in whole rat hearts indicated mitochondrial network formation and fusion activity in ventricular cardiomyocytes. Promptly after isolation, cardiomyocytes showed extensiv ...[more]

PMID: 28096338

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Project description:OBJECTIVE:Rhythmic brain stimulation has emerged as a powerful tool to modulate cognition and to target pathological oscillations related to neurological and psychiatric disorders. However, we lack a systematic understanding of how periodic stimulation interacts with endogenous neural activity as a function of the brain state and target. APPROACH:To address this critical issue, we applied periodic stimulation to a unified biophysical thalamic network model that generates multiple distinct oscillations, and examined thoroughly the impact of rhythmic stimulation on different oscillatory states. MAIN RESULTS:We found that rhythmic perturbation induces four basic response mechanisms: entrainment, acceleration, resonance and suppression. Importantly, the appearance and expression of these mechanisms depend highly on the intrinsic cellular dynamics in each state. Specifically, the low-threshold bursting of thalamocortical cells (TCs) in delta (?) oscillation renders the network relatively insensitive to entrainment; the high-threshold bursting of TCs in alpha (?) oscillation leads to widespread oscillation suppression while the tonic spiking of TC cells in gamma (?) oscillation results in prominent entrainment and resonance. In addition, we observed entrainment discontinuity during ? oscillation that is mediated by firing pattern switching of high-threshold bursting TC cells. Furthermore, we demonstrate that direct excitatory stimulation of the lateral geniculate nucleus (LGN) entrains thalamic oscillations via an asymmetric Arnold tongue that favors higher frequency entrainment and resonance, while stimulation of the inhibitory circuit, the reticular nucleus, induces much weaker and more symmetric entrainment and resonance. These results support the notion that rhythmic stimulation engages brain oscillations in a state- and target-dependent manner. SIGNIFICANCE:Overall, our study provides, for the first time, insights into how the biophysics of thalamic oscillations guide the emergence of complex, state-dependent mechanisms of target engagement, which can be leveraged for the future rational design of novel therapeutic stimulation modalities.

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Dataset Information

Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity.

Publications

Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity.

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