Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

Singh, R. P.; Bartók, Ádám; Paillard, Mélanie; Tyburski, Ashley L.; Elliott, Melanie B.; Hajnóczky, György

doi:10.1126/sciadv.abj4716

Cited by 24 publications

(19 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are several combinations of the MCUC composition that are compatible with enhanced MCU activity, which could explain the higher mitochondrial Ca 2+ uptake. As illustrated in other studies, MICU1 loss-of-function increased the basal mitochondrial Ca 2+ content ( Rao et al, 2020 ; Kohlschmidt et al, 2021 ; Singh et al, 2022 ) and PDH activity ( Rao et al, 2020 ). This could be explained by the fact that MICU1 acts as the gatekeeper of the MCU channel, limiting Ca 2+ uptake at low cytosolic Ca 2+ concentrations (<∼1, 3 μM) ( Payne et al, 2017 ).…”

Section: Discussionsupporting

confidence: 62%

IGF-1 boosts mitochondrial function by a Ca2+ uptake-dependent mechanism in cultured human and rat cardiomyocytes

Sánchez-Aguilera

López-Crisosto²,

Norambuena-Soto³

et al. 2023

Front. Physiol.

View full text Add to dashboard Cite

A physiological increase in cardiac workload results in adaptive cardiac remodeling, characterized by increased oxidative metabolism and improvements in cardiac performance. Insulin-like growth factor-1 (IGF-1) has been identified as a critical regulator of physiological cardiac growth, but its precise role in cardiometabolic adaptations to physiological stress remains unresolved. Mitochondrial calcium (Ca2+) handling has been proposed to be required for sustaining key mitochondrial dehydrogenase activity and energy production during increased workload conditions, thus ensuring the adaptive cardiac response. We hypothesized that IGF-1 enhances mitochondrial energy production through a Ca2+-dependent mechanism to ensure adaptive cardiomyocyte growth. We found that stimulation with IGF-1 resulted in increased mitochondrial Ca2+ uptake in neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes, estimated by fluorescence microscopy and indirectly by a reduction in the pyruvate dehydrogenase phosphorylation. We showed that IGF-1 modulated the expression of mitochondrial Ca2+ uniporter (MCU) complex subunits and increased the mitochondrial membrane potential; consistent with higher MCU-mediated Ca2+ transport. Finally, we showed that IGF-1 improved mitochondrial respiration through a mechanism dependent on MCU-mediated Ca2+ transport. In conclusion, IGF-1-induced mitochondrial Ca2+ uptake is required to boost oxidative metabolism during cardiomyocyte adaptive growth.

show abstract

Section: Discussionsupporting

confidence: 62%

IGF-1 boosts mitochondrial function by a Ca2+ uptake-dependent mechanism in cultured human and rat cardiomyocytes

Sánchez-Aguilera

López-Crisosto²,

Norambuena-Soto³

et al. 2023

Front. Physiol.

View full text Add to dashboard Cite

show abstract

“…That rebalancing mitochondrial calcium dynamics by removing MCU is able to rescue the lethality associated with loss of TMEM65 in the brain offers further support for the importance of TMEM65 in mediating mitochondrial calcium export. These results link disruption in mitochondrial calcium homeostasis to severe mitochondrial disease and suggest inhibition of mitochondrial calcium influx 41 may be a potential therapeutic target for defects associated with TMEM65 loss of function 1 or other diseases characterized by mitochondrial calcium overload 39,40,42,43 .…”

Section: Discussionmentioning

confidence: 88%

Loss of TMEM65 causes mitochondrial disease mediated by mitochondrial calcium

Zhang

Willingham

Reyes

et al. 2022

Preprint

View full text Add to dashboard Cite

Depletion of transmembrane protein 65 (TMEM65) in a patient with a homozygous point mutation in the TMEM65 gene splice site was reported to result in mitochondrial dysfunction and severe encephalomyopathy(1), indicating the clinical importance of TMEM65. However, the function of TMEM65 remains unknown, and the specific subcellular localization of TMEM65 to either the mitochondrial inner membrane or cardiac intercalated disc remains controversial. Here, we generated a Tmem65 reporter mouse as well as whole-body and tissue-specific Tmem65 knockout (KO) mice to investigate the localization and function of TMEM65. We show that TMEM65 is localized to mitochondria in heart, skeletal muscle, and throughout the brain. Both whole-body and nervous system-specific Tmem65 KO resulted in severe growth retardation and sudden death following seizures ~3 weeks after birth indicating TMEM65 is indispensable for normal brain function. Cardiac-specific Tmem65 KO mice were viable and fertile but had reduced mitochondrial content and cardiac stress response. Skeletal muscle-specific Tmem65 KO led to progressive, adult-onset myopathy manifested by wasting of muscle fibers, upregulation of one-carbon metabolic pathways, and reduced whole-body metabolic efficiency. These results highlight the effectiveness of a Tmem65 KO mouse model to recapitulate and further interrogate the clinical phenotypes associated with a loss of TMEM65.

show abstract

“…Indeed, loss-of-function mutations in MICU1 are associated with learning and motor deficits in humans ( Logan et al, 2014 ). Similarly, neuron-specific deletion of MICU1 in mice leads to abnormal motor and cognitive phenotypes, which are likely caused by neuronal degeneration in the spinal cord and the brain ( Liu et al, 2016 ; Singh et al, 2022 ). Mechanistically, the loss or deficit in MICU1 function results in chronic elevation of mitochondrial Ca 2+ concentration and impairment of mitochondrial Ca 2+ signaling, which leads to altered neuronal excitability, increased susceptibility to excitotoxic stress and neuronal death dependent on mitochondrial permeability transition pore ( Logan et al, 2014 ; Singh et al, 2022 ).…”

Section: Mitochondrial Ca 2+ Uptake and Release Me...mentioning

confidence: 99%

Mitochondrial calcium cycling in neuronal function and neurodegeneration

Walters

Usachev

2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca2+) buffering, and apoptotic signaling. In neurons, Ca2+ buffering is particularly important as it helps to shape Ca2+ signals and to regulate numerous Ca2+-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca2+ uniporter (MCU) and other molecular components of mitochondrial Ca2+ transport has provided insight into the roles that mitochondrial Ca2+ regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca2+ uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca2+-dependent mechanisms that drive mitochondrial dysfunction in neurologic diseases including epilepsy, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. We also consider how targeting Ca2+ uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.

show abstract

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

Cited by 24 publications

References 86 publications

IGF-1 boosts mitochondrial function by a Ca2+ uptake-dependent mechanism in cultured human and rat cardiomyocytes

IGF-1 boosts mitochondrial function by a Ca2+ uptake-dependent mechanism in cultured human and rat cardiomyocytes

Loss of TMEM65 causes mitochondrial disease mediated by mitochondrial calcium

Mitochondrial calcium cycling in neuronal function and neurodegeneration

Contact Info

Product

Resources

About