bims-miptne 2026-07-19 papers

Nat Rev Neurosci. 2026 Jul 13.

Brain mitochondria as key drivers of cognition and behaviour.

Carmen Sandi, Mary Kay Lobo, Fiona Hollis, Yusuke Hirabayashi, Jaime de Juan-Sanz, Juan P Bolaños.

Cognition and behaviour arise from computations in neural circuits, which can differ in their readiness for recruitment or in the computations and behavioural outputs that they generate. Mitochondria contribute to both circuit properties and their variability by shaping the cellular processes on which circuit function depends. Across neurons and glia, mitochondria provide bioenergetic support, regulate Ca2+ dynamics and reactive oxygen species levels, influence neurotransmitter synthesis and turnover, and sustain quality control programmes that preserve cellular integrity. The capacity of mitochondria to provide this support and their plasticity have been linked to circuit architecture, engagement and adaptation, with implications for learning and memory, reward and reinforcement, state-trait anxiety and motivation. Here we describe two complementary modes of mitochondrial support: a baseline mode, in which mitochondria sustain circuit architecture and physiological properties over long timescales, and an activity-evoked mode, in which local mitochondrial outputs support synaptic transmission and plasticity. Distinguishing these two modes helps to explain how behavioural modulators, including stress hormones, immune activity and metabolic signals, can shape behaviour by altering either baseline mitochondrial control of circuit readiness or activity-evoked mitochondrial support during circuit engagement.

DOI: https://doi.org/10.1038/s41583-026-01061-1

Science. 2026 Jul 16. 393(6808): eadx8675

A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.

The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.

DOI: https://doi.org/10.1126/science.adx8675

Mol Metab. 2026 Jul 13. pii: S2212-8778(26)00103-1. [Epub ahead of print] 102419

CaMKIIγ/δ contributes to mitochondrial metabolic adaptation in skeletal muscle during endurance training.

Ryoka Tsukahara, Yasuo Kitajima, Yuka Ichihashi, Hikaru Iwase, Shun Ohki, Yusuke Sotomaru, Tomohiro Kurosaki, Yohei Kawano, Tomoharu Yasuda.

BACKGROUND: Calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in skeletal muscle with exercise, yet its physiological role in endurance training adaptation remains unclear. This study determined whether endogenous CaMKIIγ/δ in skeletal muscle is required for endurance training-induced metabolic remodeling and exercise adaptation.
METHODS: We generated male skeletal muscle-specific CaMKIIγ/δ knockout (CaMKII mKO) mice and assessed muscle phenotype, exercise capacity, and training adaptation. Acute exercise-induced CaMKII activation was evaluated by phosphorylation status. Transcriptomic changes were analyzed by RNA sequencing before and after 4 weeks of treadmill endurance training. Mitochondrial protein abundance, ultrastructure, and bioenergetics were examined by immunoblotting, transmission electron microscopy, and Seahorse extracellular flux analysis in myotubes with acute CaMKIIγ/δ deletion.
RESULTS: Acute treadmill exercise induced CaMKII phosphorylation in muscle without altering total CaMKII abundance. CaMKII mKO mice showed normal muscle mass, grip strength, and baseline performance. However, endurance training-induced improvement in running capacity was significantly blunted. Transcriptomic analyses revealed downregulation of oxidative phosphorylation and glycolytic gene programs in CaMKII-deficient muscle at baseline and after training. OXPHOS complex protein abundance was partially reduced at baseline and markedly reduced across complexes I-V after training. CaMKII deficiency increased ultrastructurally abnormal mitochondria without reducing mitochondrial number. Consistently, CaMKII-deficient myotubes showed lower absolute per-well oxygen consumption and extracellular acidification rates.
CONCLUSIONS: In male mice, endogenous CaMKIIγ/δ in muscle is dispensable for baseline locomotor performance but essential for endurance training-induced metabolic remodeling and mitochondrial integrity. These findings support a role for CaMKII in linking contraction-induced calcium signaling to metabolic adaptation in muscle.

Keywords: CaMKII; Endurance training; Exercise adaptation; Mitochondrial metabolism; Oxidative phosphorylation; Skeletal muscle

DOI: https://doi.org/10.1016/j.molmet.2026.102419