Pharmacological inhibition of the mitochondrial Ca2+ uniporter: Relevance for pathophysiology and human therapy

Márta, Katalin; Hasan, Prottoy; Rodríguez-Prados, Macarena; Paillard, Mélanie; Hajnóczky, György

doi:10.1016/j.yjmcc.2020.09.014

Cited by 32 publications

(21 citation statements)

References 94 publications

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“…uptake and content as shown in mdx ventricular mitochondria [Figure 2; (Dubinin et al, 2020)]. This change in MICU1 expression may affect the pharmacology of MCU and should be considered for future therapeutic strategies aimed at directly targeting mitochondrial Ca 2+ uptake (Kon et al, 2017;Márta et al, 2020). The elevation of mitochondrial Ca 2+ content is therefore the result of a remodeling of the MCU complex associated with the increase in the leakage of Ca 2+ from the SR, the elevation of diastolic Ca 2+ , and the strengthening of the contact points between the two organelles.…”

Section: Discussionmentioning

confidence: 99%

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

Angebault

Panel

Lacote

et al. 2021

Front. Cell Dev. Biol.

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Besides skeletal muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibits a progressive cardiomyopathy characterized by an impaired calcium (Ca2+) homeostasis and a mitochondrial dysfunction. Here we aimed to determine whether sarco-endoplasmic reticulum (SR/ER)–mitochondria interactions and mitochondrial function were impaired in dystrophic heart at the early stage of the pathology. For this purpose, ventricular cardiomyocytes and mitochondria were isolated from 3-month-old dystrophin-deficient mice (mdx mice). The number of contacts points between the SR/ER Ca2+ release channels (IP3R1) and the porine of the outer membrane of the mitochondria, VDAC1, measured using in situ proximity ligation assay, was greater in mdx cardiomyocytes. Expression levels of IP3R1 as well as the mitochondrial Ca2+ uniporter (MCU) and its regulated subunit, MICU1, were also increased in mdx heart. MICU2 expression was however unchanged. Furthermore, the mitochondrial Ca2+ uptake kinetics and the mitochondrial Ca2+ content were significantly increased. Meanwhile, the Ca2+-dependent pyruvate dehydrogenase phosphorylation was reduced, and its activity significantly increased. In Ca2+-free conditions, pyruvate-driven complex I respiration was decreased whereas in the presence of Ca2+, complex I-mediated respiration was boosted. Further, impaired complex I-mediated respiration was independent of its intrinsic activity or expression, which remains unchanged but is accompanied by an increase in mitochondrial reactive oxygen species production. Finally, mdx mice were treated with the complex I modulator metformin for 1 month. Metformin normalized the SR/ER-mitochondria interaction, decreased MICU1 expression and mitochondrial Ca2+ content, and enhanced complex I-driven respiration. In summary, before any sign of dilated cardiomyopathy, the DMD heart displays an aberrant SR/ER-mitochondria coupling with an increase mitochondrial Ca2+ homeostasis and a complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.

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Section: Discussionmentioning

confidence: 99%

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

Angebault

Panel

Lacote

et al. 2021

Front. Cell Dev. Biol.

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“…In this respect, the recent discoveries of a specific MCU inhibitor, mitoxantrone [ 92 ], and of a membrane-permeant inhibitory Ruthenium complex named Ru265 [ 93 ] as well as of MICU1 modulators MCU-i4 and MCU-i11 [ 94 ] (for a recent review see Ref. [ 95 ]) may be of relevance, even if they have not yet been applied in the context of cancer (mitoxantrone however was developed as an anti-cancer agent and is/has been tested as such in several clinical trials). A compound named DS16570511 has also been proposed as MCUC inhibitor, but its ability to directly block the channel has not been demonstrated [ 96 ].…”

Section: Mitochondrial Ion Channels and Their Pharmacological Targeting By Small Moleculesmentioning

confidence: 99%

“…A compound named DS16570511 has also been proposed as MCUC inhibitor, but its ability to directly block the channel has not been demonstrated [ 96 ]. As pointed out by Hajnoczky and colleagues [ 95 ], these inhibitors, except MCUi11, are expected to be toxic for healthy cells as well, since they depolarize the mitochondrial membrane and cause side effects. A further inhibitor, KB-R7943, may be taken into consideration, since it has recently been shown to alleviate P. aeruginosa –triggered inflammatory responses in vivo [ 97 ], and it may have a similar anti-inflammatory effect in the tumor micro-environment, therefore negatively affecting tumor growth.…”

Section: Mitochondrial Ion Channels and Their Pharmacological Targeting By Small Moleculesmentioning

confidence: 99%

Targeting mitochondrial ion channels for cancer therapy

2021

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Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.

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“…We monitored cytosolic calcium in cultured cortical neurons at rest or upon stimulation with 50 mM KCl, in the presence or absence of chemical inhibitors of the MPC. The MCU activity was downregulated either using the pharmacological inhibitor RU360 ( Márta et al, 2021 ) or RNA interference ( Figure 6—figure supplement 2A ). These experiments showed that upon neuron depolarization with 50 mM KCl, the cytosolic calcium level was significantly higher in neurons in which MPC or MCU had been inactivated ( Figure 6C–E ; Figure 6—figure supplement 2B ).…”

Section: Resultsmentioning

confidence: 99%

Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

Rossa

Laporte

Astori

et al. 2022

eLife

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Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.

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Pharmacological inhibition of the mitochondrial Ca2+ uniporter: Relevance for pathophysiology and human therapy

Cited by 32 publications

References 94 publications

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

Targeting mitochondrial ion channels for cancer therapy

Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

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