Skeletal muscle mitoflashes, pH, and the role of uncoupling protein-3

McBride, Skye; Wei-LaPierre, Lan; McMurray, Fiona; Macfarlane, M. S.; Qiu, Xiaolin; Patten, David A.; Dirksen, Robert T.; Harper, Mary‐Ellen

doi:10.1016/j.abb.2019.01.018

Cited by 11 publications

(10 citation statements)

References 57 publications

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“…Feng et al (2019) showed a positive correlation between mitoflash and TMRM dip amplitudes for Type 1 mitoflashes, consistent with mitoflash and Ψ m depolarization being tightly coupled during these events. A similar positive correlation between mitoflash and TMRM dip amplitudes has also been reported in intact cells (Wang et al, 2016; McBride et al, 2019). Feng et al (2019) further found that the majority of Type 2 mitoflashes exhibited a prominent undershoot below baseline mt-cpYFP fluorescence following their termination when mitochondria were provided substrates for complex I (Cx I), complex II (Cx II), and ATP synthase operating in reverse (ATP hydrolysis) mode (Fig.…”

Section: Type 1 and Type 2 Mitoflashessupporting

confidence: 84%

“…In skeletal muscle fibers, CypD-dependent mPTP activity modulates mitoflash activity during muscle activity and under pathological conditions, but does not impact mitoflash activity under basal conditions (Pouvreau, 2010; Wei et al, 2011; Karam et al, 2017; Xiao et al, 2018; Wei-LaPierre et al, 2019). Furthermore, while basal mitoflash activity in skeletal muscle is unaltered by either UCP3 ablation or IMAC inhibition (Pouvreau, 2010; McBride et al, 2019), a potential regulatory role for UCP3 and IMAC under other conditions remains to be determined. Finally, other channels and exchangers that mediate ion flux across the mitochondrial inner membrane (e.g., mitochondrial Ca 2+ uniporter, K + channels, Ca 2+ /Na + exchanger, Na + /H + exchanger, and Ca 2+ (K + )/H + antiporter) may also affect the proton motive force, and thus, modulate mitoflash activity (Dzbek and Korzeniewski, 2008; Zotova et al, 2010; Boyman et al, 2013; Quan et al, 2015).…”

Section: Proton Motive Force Is the Ultimate Mitoflash Determinantmentioning

confidence: 99%

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Isolating a reverse-mode ATP synthase–dependent mechanism of mitoflash activation

Wei-LaPierre

Dirksen

2019

Journal of General Physiology

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Section: Type 1 and Type 2 Mitoflashessupporting

confidence: 84%

Section: Proton Motive Force Is the Ultimate Mitoflash Determinantmentioning

confidence: 99%

Isolating a reverse-mode ATP synthase–dependent mechanism of mitoflash activation

Wei-LaPierre

Dirksen

2019

Journal of General Physiology

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“…While overexpression of uncoupling protein type 2 (UCP2; the cardiac UCP isoform) reduces mitoflash frequency in cardiac myocytes, the effect on mitoflash duration was not reported [25,37]. We recently found that neither mitoflash frequency, amplitude, nor duration were significantly changed in FDB fibers isolated from UCP3 KO mice (the skeletal muscle UCP isoform) transiently expressing mt-cpYFP [38]. Nevertheless, further studies in intact cells and isolated mitochondria are needed to determine the role of UCP proteins in mitoflash termination.…”

Section: Discussionmentioning

confidence: 99%

Substrate-dependent and cyclophilin D-independent regulation of mitochondrial flashes in skeletal and cardiac muscle

Wei-LaPierre

Ainbinder

Tylock

et al. 2019

Archives of Biochemistry and Biophysics

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Mitochondrial flashes (mitoflashes) are stochastic events in the mitochondrial matrix detected by mitochondrial-targeted cpYFP (mt-cpYFP). Mitoflashes are quantal bursts of reactive oxygen species (ROS) production accompanied by modest matrix alkalinization and depolarization of the mitochondrial membrane potential. Mitoflashes are fundamental events present in a wide range of cell types. To date, the precise mechanisms for mitoflash generation and termination remain elusive. Transient opening of the mitochondrial membrane permeability transition pore (mPTP) during a mitoflash is proposed to account for the mitochondrial membrane potential depolarization. Here, we set out to compare the tissue-specific effects of cyclophilin D (CypD)deficiency and mitochondrial substrates on mitoflash activity in skeletal and cardiac muscle. In contrast to previous reports, we found that CypD knockout did not alter the mitoflash frequency or other mitoflash properties in acutely isolated cardiac myocytes, skeletal muscle fibers, or isolated mitochondria from skeletal muscle and the heart. However, in skeletal muscle fibers, CypD deficiency resulted in a parallel increase in both activity-dependent mitochondrial Ca 2+ uptake and activity-dependent mitoflash activity. Increases in both mitochondrial Ca 2+ uptake and mitoflash activity following electrical stimulation were abolished by inhibition of mitochondrial Ca 2+ uptake. We also found that mitoflash frequency and amplitude differ greatly between intact skeletal muscle fibers and cardiac myocytes, but that this difference is absent in isolated mitochondria. We propose that this difference may be due, in part, to differences in substrate availability in intact skeletal muscle fibers (primarily glycolytic) and cardiac myocytes (largely oxidative). Overall, we find that CypD does not contribute significantly in mitoflash biogenesis under basal conditions in skeletal and cardiac muscle, but does regulate mitoflash events during muscle activity. In addition, tissue-dependent differences in mitoflash frequency are strongly regulated by mitochondrial substrate availability.

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“…However, inhibition of UCP2 by chemical blocker or RNA interference slightly increased, rather than decreased the mitoflash incidence (Wang et al, 2017). Skeletal muscle fibers derived from UCP3 knockout mice exhibited no changes in mitoflash frequency, amplitude or duration compared to wild type controls, while the average area of mitoflash events mildly reduced (McBride et al, 2019). Thus, these functional perturbation experiments do not support the hypothesis of UCP2/3 mediated uncoupling activities as the major contributor of mitoflash signals.…”

Section: Transient Mitochondrial Ca 2+ Influx Diminishes Denervation-mentioning

confidence: 80%

Physiological Ca2+ Transients Versus Pathological Steady-State Ca2+ Elevation, Who Flips the ROS Coin in Skeletal Muscle Mitochondria

et al. 2020

Front. Physiol.

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Mitochondria are both the primary provider of ATP and the pivotal regulator of cell death, which are essential for physiological muscle activities. Ca 2+ plays a multifaceted role in mitochondrial function. During muscle contraction, Ca 2+ influx into mitochondria activates multiple enzymes related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation, resulting in increased ATP synthesis to meet the energy demand. Pathophysiological conditions such as skeletal muscle denervation or unloading also lead to elevated Ca 2+ levels inside mitochondria. However, the outcomes of this steadystate elevation of mitochondrial Ca 2+ level include exacerbated reactive oxygen species (ROS) generation, sensitized opening of mitochondrial permeability transition pore (mPTP), induction of programmed cell death, and ultimately muscle atrophy. Previously, both acute and long-term endurance exercises have been reported to activate certain signaling pathways to counteract ROS production. Meanwhile, electrical stimulation is known to help prevent apoptosis and alleviate muscle atrophy in denervated animal models and patients with motor impairment. There are various mechanistic studies that focus on the excitation-transcription coupling framework to understand the beneficial role of exercise and electrical stimulation. Interestingly, a recent study has revealed an unexpected role of rapid mitochondrial Ca 2+ transients in keeping mPTP at a closed state with reduced mitochondrial ROS production. This discovery motivated us to contribute this review article to inspire further discussion about the potential mechanisms underlying differential outcomes of physiological mitochondrial Ca 2+ transients and pathological mitochondrial Ca 2+ elevation in skeletal muscle ROS production.

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Skeletal muscle mitoflashes, pH, and the role of uncoupling protein-3

Cited by 11 publications

References 57 publications

Isolating a reverse-mode ATP synthase–dependent mechanism of mitoflash activation

Isolating a reverse-mode ATP synthase–dependent mechanism of mitoflash activation

Substrate-dependent and cyclophilin D-independent regulation of mitochondrial flashes in skeletal and cardiac muscle

Physiological Ca2+ Transients Versus Pathological Steady-State Ca2+ Elevation, Who Flips the ROS Coin in Skeletal Muscle Mitochondria

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