The regulation of ATP production by mitochondria, crucial for multicellular life, is poorly understood. Here, we investigate the molecular controls of this process in the heart and provide a framework for its Ca2+-dependent regulation. We find that the entry of Ca2+ into the matrix through the mitochondrial calcium uniporter (MCU) in the heart has neither an apparent cytosolic Ca2+ threshold nor a gating function, and guides ATP production by its influence on the inner mitochondrial membrane (IMM) potential, ΔΨm. This regulation occurs through matrix Ca2+-dependent modulation of pyruvate and glutamate dehydrogenase activity and not through any effect of Ca2+ on ATP synthase or on electron transport chain complexes II, III or IV. Examining the ΔΨm dependence of ATP production over the range of −60 mV to −170 mV in detail reveals that cardiac ATP synthase has a voltage dependence that distinguishes it fundamentally from the previous standard, the bacterial ATP synthase. Cardiac ATP synthase operates with a different ΔΨm threshold for ATP production than bacterial ATP synthase and reveals a concave-upward shape without saturation. Skeletal muscle MCU Ca2+ flux, while also having no apparent cytosolic Ca2+ threshold, is substantially different from the cardiac MCU, yet the ATP synthase voltage dependence in skeletal muscle is identical to that in the heart. These results suggest that, while the conduction of cytosolic Ca2+ signals through the MCU appears to be tissue dependent, as shown by earlier work1, the control of ATP synthase by ΔΨm appears to be broadly consistent among tissues but is clearly different from that in bacteria.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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We thank B.M. Polster, C.W. Ward, G.S.B. Williams, R.J . Khairallah and M. Karbowski for helpful suggestions. This research was supported by American Heart Association grants SDG 15SDG22100002 (to L.B.) and 16PRE31030023 (to A.P.W.); by NIH R01 HL106056, R01 HL105239, U01 HL116321, 1R01HL142290, 1 R01 HL140934 and 1R01 AR071618 (to W.J.L.); by the Medical Scientist Training Program and Training Program in Integrative Membrane Biology, NIH 2T32GM092237-06 and 5T32GM008181-28 (to A.P.W.).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
a, Timecourse of firefly luciferase luminescence signal measured from nine wells after addition of ATP to each well. In this calibration procedure, different amounts of [ATP] are added to each of the nine wells as indicated to the right of each line ([ATP]added in μM). The inset shows the measured luminescence versus [ATP]added. Purple shaded area highlights the ‘Working Range’ in which the luminescence signal is a linear function of [ATP]. b, Measurements of [ATP] produced by isolated mitochondria. The calibration procedure shown in a is used to convert the measured luminescence signal to [ATP]. The inset shows the measured mitochondrial matrix free Ca2+ concentration ([Ca2+]m) associated with the ATP measurements in b. c, ATP production rate based on the linear fit to measurements in b and scaled to units of μmol per litre cytosol per second (μM s−1, scaling is based on 80 g mitochondrial protein per litre cardiomyocyte cytosol, for more details see main methods section and Williams et. al.7) . d, The increase in [NADH] at high [Ca2+]m (>2 μM) relative to [NADH] at low [Ca2+]m (<200 nM) using the indicated combination of carbon substrates (P&M, pyruvate and malate; G&M, glutamate and malate; PC&M, palmitoylcarnitine and malate, n = 4 isolated mitochondria preparations per group, *P < 0.05 by two-sided t-test). Data are mean ± s.e.m. [Ca2+]m was measured with Rhod-2. [NADH] measurements were carried out with a luminescence assay kit (Promega, USA, for additional details see Supplementary Methods 1.4). e, Measured TMRM fluorescence ratio (F573/F46) over the maximal fluorescence ratio from the dataset. Mitochondria are exposed to 2,4-dinitrophenol ([DNP] in μM) as indicated. f, Measured extra-mitochondrial TMRM concentration. g, The mitochondrial inner membrane potential (ΔΨm) in mV is obtained from the measurements in f according to the method by Scaduto & Grotyohann32. h, ΔΨm and its corresponding TMRM fluorescence ratio. Linear fit lines are as indicated in the inset. The calibration results shown in panels e–h were verified repeatedly on a daily basis with similar results obtained. i, Excitation and emission spectra of mitochondria loaded with BCECF (2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester). 15 independents measurements are shown at the indicated pH levels (1 μM FCCP is used to equilibrate pHm and the extra-mitochondrial buffer pH) with the similar spectrum shown. j, Measured fluorescence ratio from BCECF-loaded mitochondria at the indicated mitochondrial pH values (pHm). The calibration was verified in two mitochondrial preps, with similar results. k, The pHm measurements following exposure to sodium acetate at the indicated concentrations. Data are mean ± s.e.m. (results are from 3 independent experiments in each of the indicated 7 concentrations of sodium acetate).
a, Fluo-4 Ca2+ titration curve. Shown is the fraction of Ca2+-bound fluo-4 bound at the indicated added [Ca2+]. Each point is a triplicate average. Titration curves are carried out in the indicated buffers. b, Fluo-4FF Ca2+ titration curve. Shown is the fraction of Ca2+-bound fluo-4FF at the indicated added [Ca2+]. Each point is a triplicate average. c, Rhod-2 Ca2+ titration curve. Shown is the fraction of Ca2+-bound rhod-2 at the indicated added [Ca2+]. Each point is a triplicate average. Titration is done in the absence and presence of PVP (polyvinylpyrrolidone) in the assay buffer. d, Ca2+ titration curve for fura-2AM- or rhod-2AM-loaded mitochondria. Shown is the fraction of Ca2+-bound fura-2 or rhod-2 at the indicated free Ca2+ concentration in the mitochondrial matrix ([Ca2+]m). Each point is a triplicate average. 1 μM FCCP and 1 μM of the Ca2+ ionophore ionomycin are used to equilibrate [Ca2+]m with the extra-mitochondrial free [Ca2+] (that is, [Ca2+]extra,free). The [Ca2+]extra,free is measured with fluo-5N. Equations fit to the data for a–d are detailed in the main methods section.
a, Measurements of [Ca2+]m in isolated cardiac mitochondria plotted as a function of the measured free extramitochondrial [Ca2+] (that is, [Ca2+]extra,free) in the presence of the selective MCU blocker RU360 (5 μM). Grey circles are measurements taken in the presence of pyruvate (1 mM) and malate (0.5 mM). n = 12 independent experiments. Orange circles are measurements done in the presence of glutamate (1 mM) and malate (0.5 mM). n = 12 independent experiments. [Ca2+]m was measured with fura-2 loaded into the mitochondrial matrix via its acetoxymethyl (AM) ester, [Ca2+]extra,free was measured with fluo-4 in the extra mitochondrial buffer. b, Measurements of ATP production plotted as a function of the measured [Ca2+]extra,free. The measurements of ATP production rates are normalized to the measurements at nominally zero [Ca2+]extra,free. c, ATP production at the indicated measured [Ca2+]extra,free (from experiments in a and b). Grey bars (left) are ATP production with pyruvate and malate. Orange bars (right) are ATP production with glutamate and malate. Data are mean ± s.e.m. n = 3 isolated mitochondria preparations per group (*P < 0.05 by one-way two tailed ANOVA with Bonferroni correction).
Abbreviations used: HBTU, 1-[bis(dimethylamino)methylene]-1H-benzotriazolium hexafluorophosphate 3-oxide; DIPEA, diisopropylethylamine; DMF, N,N-dimethylformamide. The detailed description of the synthesis procedure is in the methods section.
a, Time-dependent stopped-flow measurement of ΔΨm (upper panel) and of the corresponding [Ca2+]m (lower panel). In this protocol (no. 1), mitochondria were incubated with increasing extra-mitochondrial free Ca2+ and at t = 0, 500 μM [ADP] was added to the mitochondrial mix. Time-dependent depolarization of ΔΨm is shown as is the near steady-state of [Ca2+]m. Black line: [Ca2+]m= 50 nM (n = 8); turquoise: [Ca2+]m= 480 nM (n = 3); light blue: [Ca2+]m= 750 nM (n = 6); grey-blue: [Ca2+]m= 1.2 μM (n = 8); navy blue: [Ca2+]m= 1.7 μM (n = 4). b, Same as a, but in this protocol (no. 2), [Ca2+]m and [ADP] (500 μM) were increased simultaneously at t = 0 (salmon-coloured line, n = 7). The injected Ca2+ was set so that the [Ca2+]m achieved a level between 1.5 and 2 μM at 20 s. c, Same as b but in this protocol (#3), [ADP] (500 μM) rises 10 s before [Ca2+]m was increased at t = 0 (grey line, n = 6). The injected Ca2+ was set so that the [Ca2+]m achieved a level between 1.5 and 2 μM at 20 s, grey line. In a–c, the sample size (n) represents the number of independent experiments. d, The magnitude of ΔΨm depolarization in experiments a–c. The sample size is the same as in panels a–c. (* and # denotes statistical comparisons to black and beige data, respectively). e, Exponential rate constant of ΔΨm depolarization in experiments a and b. The sample size is the same as in panels a and b. In d and e, data are mean ± s.e.m.*P < 0.05, **P < 0.01, ***P < 0.001 by one-way two-tailed ANOVA with Bonferroni correction.
a,e, Representative stopped-flow time-dependent measurements of extra-mitochondrial free Ca2+ (that is, [Ca2+]extra,free). Mitochondria in uptake assay buffer (uAB) with low [Ca2+]extra,free (<100 nM) are mixed with uAB buffer with added [Ca2+] 1 ms before fluorescence measurements begin. The levels of added [Ca2+] are set so that at the beginning of the measurements the [Ca2+] added will be as indicated in the inset. In a, [Ca2+]extra,free is measured with fluo-4 in the uAB and in e with Fluo-4FF. b,f, The corresponding time-dependent measurements of matrix free Ca2+ (that is, [Ca2+]m). Insets showing the corresponding time-dependent measurements of ΔΨm. c,g, The corresponding time-dependent measurements of total extra-mitochondrial Ca2+ ([Ca2+]extra,Total). The [Ca2+]extra,Total is obtained from the fluo-4 or fluo-4FF signals (for more details see the Methods). d,h, MCU Ca2+ influx (Jmcu) is the first derivative of the [Ca2+]extra,Total. The Jmcu is scaled to units of μmol per litre cytosol per second (μM s−1, scaling is based on 80 g mitochondrial protein per litre cardiomyocyte cytosol, for more details see main methods section and Williams et. al.7). The shown stopped flow experiments were repeated independently 63 times with similar results at each [Ca2+]extra,free as indicated in Fig. 3a.
Extended Data Fig. 7 Characterization of MityCam, a mitochondrially targeted Ca2+-sensitive fluorescent-protein probe expressed in heart muscle cells.
a, MityCam fluorescence versus [Ca2+]m. Note that Ca2+ binding decreases MityCam fluorescence. Measurements are in saponin-permeabilized cardiomyocytes; [Ca2+]m is set using the Ca2+ ionophore ionomycin (2 μM). The extracellular (bath) solution contains Rhod-2 (tripotassium salt, cell-impermeant) to measure the bath [Ca2+], a proton ionophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 500 nM) to set the mitochondrial pH, rotenone (400 nM) to block the ETC and the production of reactive oxygen species, and oligomycin (5 mM) to block reverse-mode consumption of ATP by the ATP synthase, pH 7.8. Fit curve is a single-site binding model (n = 30 cells). b, Top: Confocal line-image from an intact cardiomyocyte expressing MityCam. Bottom: The time-course of changes in [Ca2+]m from the confocal fluorescence measurements. Caffeine (10 mM) was applied for 10 s via a local micro-perfusion system to rapidly trigger Ca2+ release from the sarcoplasmic reticulum at the indicated times (highlighted with grey shading). The experiment was repeated independently with n = 10 cells with similar results. c, The average time-course of changes in [Ca2+]m following caffeine applications. d, Confocal line-image from an intact cardiomyocyte expressing MityCam in a bath solution devoid of Ca2+ (chelated by 1 mM EGTA) and treated with thapsigargin (1 μM) for 10 min prior to imaging to deplete the sarcoplasmic reticulum of Ca2+. Top panel shows MityCam fluorescence; middle panel shows the fluorescence of sulforhodamine (sulforhodamine is included in the micro-perfusion solution to indicate the exact duration of 10 mM caffeine application). Lower panel shows the time-course of changes in [Ca2+]m from the confocal fluorescence measurements. Note that throughout the entire time course of the experiment the extracellular solution is devoid of Ca2+ and also contains 1 μM thapsigargin. The experiment was repeated independently with n = 11 cells with similar results. e, Confocal images of cardiac mitochondria isolated from MityCam expressing cardiomyocytes. f, Measurements of [Ca2+]m from isolated single mitochondria expressing MityCam. Top panel (i) shows MityCam fluorescence; lower panel (ii) shows sulforhodamine fluorescence, which indicates the duration of micro-perfusion of 100 μM Ca2+ (see bars above the top panel). Mitochondria isolated from MityCam-expressing cardiomyocytes are adhered to a glass coverslip for confocal microscopy measurements. Rapid step (2–3 ms rise time) of [Ca2+] from 0 (1 mM EGTA) to 100 μM is achieved via a micro-perfusion system. Sulforhodamine is included in the solution applied via the micro-perfusion system to indicate when a mitochondrion is exposed to the solution containing 100 μM Ca2+. The experiment in e and f were repeated independently with n = 18 mitochondria with similar results. g, The average time-course of changes in [Ca2+]m following the step increase of Ca2+ from 0 to 100 μM (black line). h, Same as g but for comparison to another Ca2+ sensitive fluorescent indicator, MityCam-expressing mitochondria are also loaded with the fluorescent Ca2+ indicator Rhod-2 via its acetoxymethyl (AM) ester form (Rhod-2 AM). To accelerate the rate of [Ca2+]m rise [Ca2+] is raised to 1 mM, all solutions also contain ionomycin (5 μM), FCCP (5 μM), oligomycin (1 μM), pH = 7.8. Green trace for MityCam (n = 12 mitochondria) and red for Rhod-2 (n = 9 mitochondria). The time at which 1 μM [Ca2+]m is measured is indicated by arrows, this time point is obtained by converting the shown fit lines to units of μM [Ca2+]m. For additional details see Boyman et al., 2014 (ref. 37).
Extended Data Fig. 8 MCU conductance and voltage dependence of ATP production in heart and skeletal muscle.
a, Measurement of the MCU-dependent Ca2+ influx (Jmcu) (nmole mg−1 s−1) in cardiac mitochondria (green circles, from Fig. 3), skeletal muscle (black circles), and skeletal muscle with Ru360 (5 μM) (red circles) is plotted as a function of measured [Ca2+]i (n = 63, n = 87, and n = 12 independent experiments, respectively, each with [Ca2+]i, [Ca2+]m and ΔΨm measured). Linear least-squares fit to the heart mitochondria data is shown (slope = 0.015). b, MCU conductance (G) for each measurement shown in a normalized to the minimal conductance (Gmin) of the cardiac dataset (G/Gmin) plotted as a function of [Ca2+]i. Linear least-squares fit line to the heart mitochondria data is shown (slope = 6.1). c, Relative number of open MCUs per mitochondrion plotted as a function of [Ca2+]I, taken from b after dividing by the [Ca2+]i-dependent unitary conductance of MCU and normalized to the minimal number of open MCUs of the cardiac dataset. Linear least-squares fit to the heart mitochondria data is shown (slope = 0.051, intercept = 3.3). For skeletal muscle data under [Ca2+]i of 1.5 μM the measurements were done using stopped flow as described in Extended Data Fig. 5. Jmcu at [Ca2+]i above 1.5 μM was collected using a multi-well-plate reader with ΔΨm set using a K+ gradient and the K+ ionophore valinomycin. Skeletal muscle data is fit to a modified Hill equation with a K0.5 of 7.9 μM and a Hill coefficient of 2.95. d, The dependence of ATP production on ΔΨm in the absence of carbon substrates and at [Ca2+]m < 200 nM. The measurements of ATP production rates are normalized to the minimal production rate of each dataset. Measurements from heart mitochondria are shown in green circles (n = 77, replotted from Fig. 4a), the measurements from skeletal muscle mitochondria are in shown in black circles (n = 45 independent experiments). ΔΨm was set by using a fixed K+ gradient and the K+ ionophore valinomycin (see Methods).
Supplementary Figs. 1 and 2, and Discussion
Supplementary Tables containing statistical information
Supplementary Video 1 Video-based measurements of sarcomere length from cardiomyocyte contracting in PVA hydrogel
Video recording of contracting cardiomyocyte embedded in and cross-linked to the PVA hydrogel (captured at 300 Hz frame-rate). Dynamic video-based sarcomere length measurements in μm are carried out from the highlighted black rectangular frame with the 900B:VSL system (Aurora Scientific, Canada). Field electrical stimulation (40 Volt cm–1) to trigger contraction at either 1 Hz or 8 Hz was done using MyoPacer (Ion Optix, USA).
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Wescott, A.P., Kao, J.P.Y., Lederer, W.J. et al. Voltage-energized calcium-sensitive ATP production by mitochondria. Nat Metab 1, 975–984 (2019). https://doi.org/10.1038/s42255-019-0126-8
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