Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment

Balderas, Enrique; Eberhardt, David; Lee, Sandra; Pleinis, John M.; Sommakia, Salah; Balynas, Anthony; Yin, Xiushan; Parker, Mitchell C; Maguire, Colin T.; Cho, Scott; Szulik, Marta W.; Bakhtina, Anna; Bia, Ryan; Friederich, Marisa W.; Locke, Timothy M.; Hove, Johan L.K. Van; Drakos, Stavros G.; Sancak, Yasemin; Tristani-Firouzi, Martin; Franklin, Sarah; Rodan, Aylin R.; Chaudhuri, Dipayan

doi:10.1038/s41467-022-30236-4

Cited by 26 publications

(33 citation statements)

References 81 publications

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“…We suggest that this could induce further mitochondrial compensation via failure to properly engage the MCU. Calcium entry via the MCU preserves energy synthesis when the electron transport chain is impaired (Balderas et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Miro1 R272Q disrupts mitochondrial calcium handling and neurotransmitter uptake in dopaminergic neurons

Schwarz

Sharma

Dodi

et al. 2022

Front. Mol. Neurosci.

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The Rho GTPase Miro1, located at the mitochondrial outer membrane is known to properly distribute mitochondria to synapses, aid calcium buffering and initiate PINK1-Parkin mediated mitophagy. Several heterozygous RHOT1/Miro1 variants were identified in sporadic Parkinson’s disease patients. Miro1 R272Q is located within a calcium binding domain, but the functional outcome of this point mutation and its contribution to the development of disease are unclear. To address this, we introduced a heterozygous RHOT1/Miro1 R272Q point mutation in healthy induced pluripotent stem cells. In dopaminergic neurons, Miro1 R272Q does not affect Miro1 protein levels, CCCP-induced mitophagy, nor mitochondrial movement yet causes the fragmentation of mitochondria with reduction of cristae and ATP5A. Inhibition of the mitochondrial calcium uniporter phenocopied Miro1 R272Q cytosolic calcium response to Thapsigargin in active neurons, a similar effect was observed during the calcium buffering phase in Miro1 knockdown neuroblastoma cells. Altered mitochondrial calcium regulation is associated with reduced mitochondrial respiration and reduced catecholamine neurotransmitter uptake. Synaptic changes are not coupled to dopamine distribution or dopamine transporters but are linked to Miro1 R272Q-related calcium handling via the mitochondria concomitant with defective dopamine regulation at the mitochondrial surface by monoamine oxidase. We conclude that the Miro1 R272Q heterozygous point mutation dampens mitochondrial-calcium regulation and mitochondrial capacity via events at the outer membrane that are sufficient to disrupt dopaminergic function.

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Section: Discussionmentioning

confidence: 99%

Miro1 R272Q disrupts mitochondrial calcium handling and neurotransmitter uptake in dopaminergic neurons

Schwarz

Sharma

Dodi

et al. 2022

Front. Mol. Neurosci.

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“…To more directly assess the effect of PE on UCP1 activity, we quantified UCP1-dependent proton current in mitoplasts prepared from BAT mitochondria in control and PSD-iBKO mice (Figure 6A) (Balderas et al, 2022; Fedorenko et al, 2012). IMM portion of mitoplasts were patch-clamped to perform electrophysiologic measurements of proton current through UCP1 (Figure 6B).…”

Section: Resultsmentioning

confidence: 99%

“…5 week old mice were sacrificed (CO 2 asphyxiation) followed by cervical dislocation. Interscapular BAT was manually separated, and mitochondria were isolated as described in (Balderas et al, 2022). Tissue was disrupted with a Potter-Elvehjem homogenizer, and a crude mitochondrial fraction isolated by differential centrifugation.…”

Section: Protein Analysismentioning

confidence: 99%

Mitochondrial Phosphatidylethanolamine Directly Regulates UCP1 to Promote Brown Adipose Thermogenesis

Johnson

Peterlin

Balderas

et al. 2022

Preprint

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Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of ATP synthase. Here we provide evidence that mitochondrial phosphatidylethanolamine (PE) directly regulates UCP1-dependent proton conductance across IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PSD-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.

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“…Although we saw no evidence of altered mitochondrial function in juvenile mdx FDB fibres, mitochondrial anomalies are well reported in animal models of DMD and patients, including in muscle stem cells (reviewed in (34) and (51)). Complex I dysfunction has been reported in isolated mitochondria and fibres from mdx mouse muscle using different methodological approaches (36, 52, 53) and is probably linked to intracellular/mitochondrial calcium dysregulation as was reported mechanistically only recently (54). However, ATP production/phosphorylating respiration can be restored by re-routing respiration through Complex II (via addition of succinate and Complex I inhibitors (36, 52)).…”

Section: Discussionmentioning

confidence: 97%

Dimethyl fumarate modulates the Duchenne muscular dystrophy disease program following short-term treatment in mdx mice

Timpani

Kourakis

Debruin

et al. 2022

Preprint

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New medicines are urgently required to treat the fatal neuromuscular disease, Duchenne muscular dystrophy (DMD). DMD involves progressive muscle damage and weakness, which are preceded by oxidative stress, inflammation, and mitochondrial dysfunction. Dimethyl fumarate (DMF) is a potent small molecule nuclear erythroid 2-related factor 2 (Nrf2) activator with current clinical utility in the treatment of multiple sclerosis and psoriasis. Pharmaceutical targeting of Nrf2 by DMF has strong translational potential for DMD, given it: (1) promotes antioxidant defence systems; (2) has a potent immuno-modulatory profile; and (3) can be rapidly re-purposed into clinical care strategies for DMD patients. Here, we tested two weeks of daily 100mg/kg DMF versus 5mg/kg standard care prednisone (PRED) treatment during the peak muscle degeneration period in juvenile mdx mice, the gold standard murine DMD model. Both drugs modulated seed genes driving the DMD disease program and improved muscle force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects that protected contracting muscles from fatigue, improved histopathology and augmented clinically compatible muscle function tests. In contrast, PRED treatment stunted mouse growth, worsened histopathology and modulated many normally expressed inflammatory and extracellular matrix (ECM) genes consistent with pan immunosuppression. These findings suggest DMF could be a more selective modulator of the DMD disease program with better efficacy and fewer side effects than standard care PRED therapy warranting follow-up studies to progress clinical translation.

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Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment

Cited by 26 publications

References 81 publications

Miro1 R272Q disrupts mitochondrial calcium handling and neurotransmitter uptake in dopaminergic neurons

Miro1 R272Q disrupts mitochondrial calcium handling and neurotransmitter uptake in dopaminergic neurons

Mitochondrial Phosphatidylethanolamine Directly Regulates UCP1 to Promote Brown Adipose Thermogenesis

Dimethyl fumarate modulates the Duchenne muscular dystrophy disease program following short-term treatment in mdx mice

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