Researcher discovers caloric restriction triggers neurodegeneration with mitochondrial DNA depletion by altering ER-mitochondria calcium transfer

Mitochondrial DNA (mtDNA) mutations and depletion are key contributors to mitochondrial epilepsy and neurodegeneration, yet mechanistic studies and therapy development are hindered by the lack of suitable models. While caloric restriction (CR) shows neuroprotective effects in general contexts, its impact under mitochondrial dysfunction remains unclear, raising important concerns about its clinical application in mtDNA-related neurological diseases and highlighting a critical gap in current understanding.

On June 3, 2025, a research team led by LIU Xingguo from the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, published a paper titled "Glucose restriction induces degeneration of neurons with mitochondrial DNA depletion by altering ER-mitochondria calcium transfer" in the journal Molecular Psychiatry. The team revealed that CR induces neurodegeneration in neurons with mitochondrial DNA (mtDNA) depletion by disrupting calcium transfer between the endoplasmic reticulum (ER) and mitochondria. This pathological calcium signaling causes early motor dysfunction, accelerated epilepsy progression, and aggravated neuronal damage. The study also established the first human neuronal and mouse models of mitochondrial epilepsy, providing crucial platforms for mechanistic research and therapeutic development, while raising concerns about the safety of CR in patients with mtDNA depletion disorders.

Using PHP.eB vectors to deliver the HSV-1 UL12.5 protein, which targets mitochondria to induce selective mtDNA depletion, the researchers generated a mouse model exhibiting hallmark epileptic features. Electroencephalogram (EEG) recordings showed increased epileptic discharges, and patch-clamp studies revealed neuronal hyperexcitability characterized by reduced sodium and potassium currents and elevated excitatory synaptic activity. Complementing this, an mtDNA-depleted human iPSC-derived neuronal model treated with 2-deoxyglucose (2-DG), a CR mimetic, displayed pronounced neurodegeneration, synaptic loss, and axonal fragmentation, independent of mitochondrial membrane potential collapse or transport defects.

Mechanistically, super-resolution microscopy and the Split-GFP system uncovered increased ER-mitochondria contacts in mtDNA-depleted neurons. Under CR, calcium imaging revealed depletion of ER calcium stores and excessive mitochondrial calcium uptake, causing intracellular calcium overload. Intracellular calcium chelation rescued neurons, while extracellular calcium removal did not, confirming the intracellular origin of calcium dysregulation. Pharmacological inhibition of ER calcium channels (RyR and IP3R antagonists) prevented 2-DG-induced degeneration, demonstrating that excessive ER-mitochondria calcium transfer drives neurotoxicity. In vivo, fasting worsened seizures and gliosis in mtDNA-depleted mice, effects reversed by the IP3R inhibitor 2-APB, suggesting therapeutic potential in targeting ER-mitochondria calcium signaling. This work not only identifies a novel neurodegenerative pathway linked to mitochondrial dysfunction and metabolic stress but also challenges the universal benefits of caloric restriction, emphasizing caution in its use for mitochondrial epilepsy and related disorders.

This study was completed in collaboration with multiple research groups, including Jinan University, Innovation Center for Regenerative Medicine and Health at Hong Kong Institute of Innovation under Chinese Academy of Sciences, Guangzhou Medical University and Chinese University of Hong Kong.

Figure: Caloric restriction induces neurodegeneration in mtDNA-depleted neurons by altering ER-mitochondria calcium transfer (Image by Prof. LIU's team).

Contacts:

LIU Xingguo, Ph.D., Principal Investigator;

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China, 510530.

Email: liu_xingguo@gibh.ac.cn