Mitochondria are recognized as pivotal regulators in cell fate determination, and their dysfunction is implicated in numerous major diseases. While mitochondria control classical programmed cell death pathways, including apoptosis, necroptosis, and pyroptosis, the recent identification of mitoxyperiosis, a BAX/BAK1/BID-dependent and spatially restricted mode of oxidative death, has added complexity to this regulatory framework. Nonetheless, a systematic understanding of how mitochondria coordinate these diverse pathways, particularly the mechanistic relationship between canonical death pathways and this newly identified mode, remains insufficiently explored. In this review, we address three fundamental questions: (1) Through which key molecular mechanisms, including mitochondrial outer membrane permeabilization, reactive oxygen species bursts, mitochondrial DNA release, and alterations in mitochondrial dynamics, do mitochondria regulate each major death pathway? (2) How does mitoxyperiosis diverge from and intersect with classical ferroptosis and other death modalities, and what unique features characterize its execution? (3) What therapeutic opportunities and challenges emerge from targeting mitochondrial death checkpoints to protect cells in pathological conditions and to treat cancer? By critically integrating current evidence, we propose a comprehensive framework that elucidates the regulatory logic of mitochondria-mediated cell death and underscores mitochondrial plasticity as a crucial determinant of cellular outcomes. This perspective not only clarifies the integrative role of mitochondria within the cell death network but also suggests new avenues for developing precision therapies for diseases associated with mitochondrial dysfunction.

Acute ischemic stroke elicits a robust inflammatory response within the brain. As one of the first peripheral immune cells to infiltrate the ischemic parenchyma, neutrophils show high heterogeneity and engage in complex crosstalk with resident brain cells. In this review, we first delineate the temporal dynamics of neutrophil mobilization after ischemic stroke, emphasizing their early and sustained accumulation in the ischemic brain. We then highlight recent advances in understanding neutrophil heterogeneity following ischemic stroke, with a particular focus on the skull-brain axis revealed by single-cell RNA sequencing. Additionally, we discuss the multifaceted interactions between neutrophils and parenchymal cells, including endothelial cells, neurons, microglia, and astrocytes after ischemic stroke. Finally, we expand the translational perspective by discussing emerging therapeutic approaches targeting neutrophils, NETosis, or specific neutrophil subsets in ischemic stroke. Unlike prior reviews that broadly focused on inflammatory networks, the present review specifically emphasizes the crosstalk between distinct neutrophil subsets and cerebral-resident cells, and integrates the latest single-cell RNA sequencing discoveries, including the newly identified skull-brain axis and a critical discussion of dichotomous models. Collectively, a comprehensive understanding of this intricate cellular network may help elucidate neutrophil heterogeneity, and future therapeutic strategies should shift from broad neutrophil depletion to precise targeting of pathogenic subsets to preserve potential repair functions.

Kim and colleagues report a finding that is easy to understate: thalamic hyperconnectivity with sensorimotor and visuo-occipital cortices, present in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at baseline, shifts back toward the pattern seen in healthy controls after hyperbaric oxygen therapy and does so most in the patients who improve clinically. To my knowledge, this is the first treatment-coupled, apparently reversible thalamocortical signature in ME/CFS. Viewed through predictive processing (the framework in which the brain continually predicts its own sensory and bodily inputs), the thalamus is theorised to be a gain-control gate that helps set the precision or weight assigned to ascending bodily signals. I argue that the baseline hyperconnectivity reflects deficient filtering of expected input, and that its post-treatment reduction may index restored filtering. The same failure of attenuation offers a parsimonious account of several symptoms that often co-occur in patients, including sensory hypersensitivity, pain, orthostatic intolerance, and cognitive "brain fog", as one mechanism expressed across exteroceptive, nociceptive, autonomic, and cognitive domains. Because hyperbaric oxygen therapy is a vascular intervention and resting-state connectivity is an indirect measure this gain interpretation remains a hypothesis and I outline how it can be tested across exertion and post-exertional malaise rather than at baseline alone.