Mitochondrial respiratory chain complexes play important roles in energy production via oxidative phosphorylation (OXPHOS) to drive various biochemical processes in eukaryotic cells. These processes require coordination with other cell organelles, especially the nucleus. Factors encoded by both nuclear and mitochondrial DNA are involved in the formation of active respiratory chain complexes and ‘supercomplexes’, the higher-order structures comprising several respiratory chain complexes. Various nuclear hormone receptors are involved in the regulation of OXPHOS-related genes. In this article, we review the roles of nuclear steroid receptors (NR3 class nuclear receptors), including estrogen receptors (ERs), estrogen-related receptors (ERRs), glucocorticoid receptors (GRs), mineralocorticoid receptors (MRs), progesterone receptors (PRs), and androgen receptors (ARs), in the regulatory mechanisms of mitochondrial respiratory chain complex and supercomplex formation.

The mitochondrial electron transport chain (ETC) plays an essential role in energy production by inducing oxidative phosphorylation (OXPHOS) to drive numerous biochemical processes in eukaryotic cells. Disorders of ETC and OXPHOS systems are associated with mitochondria- and metabolism-related diseases, including cancers; thus, a comprehensive understanding of the regulatory mechanisms of ETC and OXPHOS systems is required. Recent studies have indicated that noncoding RNAs (ncRNAs) play key roles in mitochondrial functions; in particular, some ncRNAs have been shown to modulate ETC and OXPHOS systems. In this review, we introduce the emerging roles of ncRNAs, including microRNAs (miRNAs), transfer-RNA-derived fragments (tRFs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), in the mitochondrial ETC and OXPHOS regulation.

Despite a long history of research, neurodegenerative diseases and malignant brain tumor gliomas are both considered incurable, facing challenges in the development of treatments. Recent evidence suggests that RNA modifications, previously considered as static components of intracellular RNAs, are in fact dynamically regulated across various RNA species in cells and play a critical role in major biological processes in the nervous system. Innovations in next-generation sequencing have enabled the accurate detection of modifications on bases and sugars within various RNA molecules. These RNA modifications influence the stability and transportation of RNA, and crucially affect its translation. This review delves into existing knowledge on RNA modifications to offer a comprehensive inventory of these modifications across different RNA species. The detailed regulatory functions and roles of RNA modifications within the nervous system are discussed with a focus on neurodegenerative diseases and gliomas. This article presents a comprehensive overview of the fundamental mechanisms and emerging roles of RNA modifications in these diseases, which can facilitate the creation of innovative diagnostics and therapeutics for these conditions.

Aerobic muscle activities predominantly depend on fuel energy supply by mitochondrial respiration, thus, mitochondrial activity enhancement may become a therapeutic intervention for muscle disturbances. The assembly of mitochondrial respiratory complexes into higher-order “supercomplex” structures has been proposed to be an efficient biological process for energy synthesis, although there is controversy in its physiological relevance. We here established Förster resonance energy transfer (FRET) phenomenon-based live imaging of mitochondrial respiratory complexes I and IV interactions using murine myoblastic cells, whose signals represent in vivo supercomplex assembly of complexes I, III, and IV, or respirasomes. The live FRET signals were well correlated with supercomplex assembly observed by blue native polyacrylamide gel electrophoresis (BN-PAGE) and oxygen consumption rates. FRET-based live cell screen defined that the inhibition of spleen tyrosine kinase (SYK), a non-receptor protein tyrosine kinase that belongs to the SYK/ zeta-chain-associated protein kinase 70 (ZAP-70) family, leads to an increase in supercomplex assembly in murine myoblastic cells. In parallel, SYK inhibition enhanced mitochondrial respiration in the cells. Notably, SYK inhibitor administration enhances exercise performance in mice. Overall, this study proves the feasibility of FRET-based respirasome assembly assay, which recapitulates in vivo mitochondrial respiration activities.

Alzheimer’s Disease (AD) management is challenging due to limitations in detection methods. Currently, cerebrospinal fluid (CSF) biomarkers involve assessing β-amyloid (Aβ) and phosphorylated tau proteins. The lumbar puncture procedure to obtain CSF is invasive and sometimes causes significant anxiety in patients. In contrast, plasma biomarkers would allow rapid, accurate, and cost-effective diagnosis, while minimizing invasiveness and discomfort. Using a dataset involving 120 plasma proteins from clinically diagnosed AD patients versus cognitively normal subjects, we developed classification models by applying various machine learning algorithms (EBlasso, EBEN, XGBoost, LightGBM, TabNet, and TabPFN) to plasma proteomic measurements. Gene ontology and pathway enrichment, and a literature review were used to evaluate the potential relevance of the biomarkers identified in AD-related mechanisms. Biomarkers identified were also evaluated for the enrichment of aging-related biomarkers. The models developed yielded high AUROC and accuracy, mostly >0.9. Proteins selected as predictors by all the models included Angiopoietin-2 (ANG-2), epidermal growth factor (EGF), Interleukin 1α (IL-1α), and platelet growth factor subunit B (PDGF-BB). Ample previous literature supported their relevance in AD. The pool of all the biomarkers identified was significantly enriched with known aging-related biomarkers (p = 0.040). Applying cutting-edge algorithms is expected to be advantageous for developing AD prediction models with plasma proteomic data, and future large studies to externally validate the constructed models in other populations to assess their generalizability is important. The proteins uncovered may represent novel preventative or therapeutic targets.

Tauopathies, including Alzheimer's disease (AD), are driven by pathological Tau aggregation, a process that requires co-factors. Small RNAs (sRNA) have been proposed as such co-factors, yet little is known about endogenous transcripts that promote Tau pathology. We identify stress-induced tRNA-derived RNAs or fragments (tDRs/tRFs) as the most dysregulated sRNA class in human AD brains, PS19 mice overexpressing mutant human Tau, and human neuronal tauopathy models. Notably, the highly accumulating 5′GluCTC and 5′GlyGCC tRFs induce Tau S396 phosphorylation, oligomerization, and impact neurite growth. Moreover, 5′GluCTC is enriched in pathological Tau precipitates and co-localizes with oligomeric Tau in PS19 mouse brains. Inhibiting 5′GluCTC mitigates Tau pathology. Furthermore, these tRFs are highly secreted by stressed neurons and can be taken up by recipient cells, implicating them in the propagation of pathology. Our findings establish 5′GluCTC as a key regulator of Tau aggregation and suggest its inhibition as a promising therapeutic strategy for tauopathies.