Nuclear Stress Bodies and Mitochondrial Signal Transduction Regulate Thermotolerance in Cattle: Insights Into Molecular Mechanisms.

Heat stress represents a major threat to cattle productivity, welfare, immune competence, and sustainability under climate change. Although genomic studies have identified loci associated with thermoregulatory traits, sequence variation alone does not explain the rapid, reversible cellular adaptations required during acute thermal challenge. Increasing evidence suggests that thermotolerance depends on coordinated regulation between nuclear transcriptional architecture and mitochondrial metabolic stability. This review synthesizes mechanistic insights into two interconnected regulatory axes: heat shock factor 1 (HSF1)-dependent nuclear stress body (nSB) formation and mitochondrial-nuclear signaling. During thermal exposure, HSF1 reorganizes chromatin through phase-separated nuclear condensates, amplifying stress-inducible transcription. Concurrently, mitochondrial perturbation alters reactive oxygen species production, calcium flux, and ATP availability, thereby influencing chromatin accessibility and transcription factor activity. Experimental studies in mammalian systems demonstrate that oxidative signaling modulates HSF1 DNA-binding competence, while mitochondrial metabolites regulate histone acetylation and demethylation, linking energetic status to transcriptional plasticity. These cross-compartmental processes determine whether cells maintain proteostasis and recover or progress toward apoptotic and inflammatory outcomes. Although direct characterization in cattle remains limited, breed-level differences in heat shock protein induction, mitochondrial ROS handling, and mtDNA haplotypes suggest meaningful variation in regulatory resilience. The efficiency of coordination between nuclear activation and mitochondrial stabilization may therefore represent a critical determinant of thermotolerance. We further frame thermotolerance as a resource-allocation trait, reflecting energetic partitioning among milk synthesis, immune function, reproduction, and stress protection in high-producing dairy cattle. Understanding these cross-compartmental regulatory mechanisms may support future studies identifying biomarkers and genomic targets for improving heat resilience in cattle.