Mitochondria are crucial organelles for cellular homeostasis, regulating processes such as ATP production, reactive oxygen species (ROS) management and Ca²⁺ signaling. In particular, mitochondrial Ca²⁺ plays a dual role: enabling physiological functions like metabolism and ATP synthesis while contributing to pathological processes such as apoptosis and oxidative stress when dysregulated. The balance of mitochondrial Ca²⁺ is maintained through interactions between uptake and efflux mechanisms. Key players in the process include the mitochondrial calcium uniporter (MCU) complex for Ca²⁺ influx and the Na⁺/Ca²⁺ exchanger (NCLX) for efflux. The mitochondria-endoplasmic reticulum contact sites (MERCS) also play a pivotal role in facilitating Ca²⁺ transfer. Dysregulation at any level, such as excessive uptake or impaired efflux, leads to mitochondrial Ca²⁺ overload, triggering ROS production, mitochondrial membrane potential loss, and permeability transition pore activation, which can culminate in cell death.

A review by a team of researchers at the Chinese Academy of Science highlights the role of mitochondrial Ca²⁺ imbalance in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias (SCAs).

In AD, amyloid-beta (Aβ) disrupts mitochondrial Ca²⁺ homeostasis by enhancing Ca²⁺ uptake via MCU and impairing efflux through NCLX. These changes lead to ROS accumulation, energy depletion, and neuronal death. MERCS alterations exacerbate the pathology by increasing ER-mitochondria Ca²⁺ transfer.

In PD, α-synuclein aggregates disrupt MERCS, impairing Ca²⁺ transfer from the ER to mitochondria, while DJ-1 mutations reduce the antioxidant capacity, exacerbating oxidative stress. Mutations in several ALS-associated genes, including TAR DNA-binding protein 43 (TDP-43), superoxide dismutase 1 (SOD1), and C9orf72, have been reported to physically interact with the mitochondria and play pivotal roles in maintaining mitochondrial function.

Meanwhile, HD is caused by the expansion of CAG repeats in the huntingtin (HTT) gene, producing mutant huntingtin (mHTT) protein. In HD, mHTT increases the sensitivity of IP₃R and NMDA receptors, causing abnormal cytosolic/mitochondrial Ca²⁺ signaling and mitochondrial dysfunction.

As for SCAs, they are a group of inherited neurodegenerative disorders caused by polyglutamine expansions in genes such as ATXN2 and ATXN3. Mutant proteins enhance IP₃R-mediated Ca²⁺ release from the ER, resulting in excessive mitochondrial Ca²⁺ uptake and impaired efflux.

The review, published in the KeAi journal Mitochondrial Communications, also discusses the potential interventions targeting mitochondrial Ca²⁺ regulators. Strategies include modulating MCU and NCLX activity, stabilizing MERCS, and developing compounds that prevent mitochondrial Ca²⁺ overload. For instance, inhibitors of MCU and stabilizers of mitochondrial permeability transition pore (mPTP) show promise in preclinical models.

“In this review, we emphasize the role of Ca²⁺_mito in both physiological and pathophysiological contexts,” says the corresponding author Tie-Shan Tang. “Developing drugs that specifically target parts of the MCU complex, NCLX, or MERCS is tricky. Hence, we need sufficient information to ensure they only affect mitochondrial Ca²⁺ levels where needed, without messing up the healthy tissues”.

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References

DOI

10.1016/j.mitoco.2025.01.001

Original Source URL

https://doi.org/10.1016/j.mitoco.2025.01.001

Funding information

National Natural Science Foundation of China (Grant Nos. 8203003, 92254301, 81921006, 32070780), the National Key R&D Program of China (2023YFA1801900), the Key Laboratory of Organ Regeneration and Reconstruction, and the State Key Laboratory of Membrane Biology.

Journal

Mitochondrial Communications