Oxidative stress (OS) is an important factor in the pathophysiology of numerous neurodegenerative disorders, such as Parkinson's disease, multiple sclerosis, cerebrovascular pathology or Alzheimer's disease. OS also significantly influences progression among the various neurodegenerative disorders. The imbalance between the formation of reactive oxygen species (ROS) and the body's capacity to neutralize these toxic byproducts renders the brain susceptible to oxidative injury. Increased amounts of ROS can result in cellular malfunction, apoptosis and neurodegeneration. They also represent a substantial factor in mitochondrial dysfunction, a defining characteristic of neurodegenerative disorders. Comprehending the fundamental mechanisms of OS and its interactions with mitochondrial function, neuroinflammation and cellular protective pathways becomes essential for formulating targeted therapeutics to maintain brain health and reduce the impacts of neurodegeneration. We address recent highlights on the role of OS in brain function in terms of significance for neuronal health and the progression of neurodegenerative disorders.

Impaired mitochondrial bioenergetics in macrophages can drive hyperinflammatory cytokine responses 1–6 , but whether this may also be caused by inherited mtDNA mutations is unknown. Here, we address this question using a multi-omic approach that integrates super-resolution imaging and metabolic analyses to profile macrophages from a mouse model of mitochondrial disease arising from a heteroplasmic mutation (m.5019A>G) in the mitochondrial tRNA for alanine 7 . These m.5019A>G macrophages exhibit defects in respiratory chain complexes and oxidative phosphorylation (OxPhos) due to decreased intra-mitochondrial translation. To adapt to this metabolic stress, mitochondrial fusion, reductive glutamine metabolism, and aerobic glycolysis are all increased. Upon inflammatory activation, type I interferon (IFN-I) release is enhanced, while the production of pro-inflammatory cytokines and oxylipins are restrained in m.5019A>G macrophages. Finally, an in vivo endotoxemia model using m.5019A>G mice reveal elevated IFN-I levels and sickness behaviour. In conclusion, our study identifies an unexpected imbalance in innate immune signalling in response to a pathogenic mtDNA mutation, with important implications for the progression of pathology in patients with mtDNA diseases 8 .

Our study explores the complex dynamics of the integrated stress response (ISR) axis, highlighting PIM2 kinase's critical role and its interaction with the BCL2 protein family, uncovering key mechanisms of cell survival and tumor progression. Elevated PIM2 expression, a marker of various cancers, often correlates with disease aggressiveness. Using a model of normal and malignant plasma cells, we show that inhibiting PIM2 kinase inhibits phosphorylated BAD production and activates ISR-mediated NOXA expression. This shift towards MCL1 dependence underscores the synergy achieved through combined PIM/MCL1 inhibition, driven largely by ISR-mediated NOXA expression. In mouse xenograft models, dual targeting of PIM2 and MCL1 effectively controls tumor growth-a response reversed by ISR-specific inhibition and upregulation of genes linked to tumor cell dissemination. This work elucidates the molecular intricacies of PIM2 inhibition and its implications for cancer therapy, especially in tumors with elevated PIM2 expression.
© 2024. The Author(s).

Post-translational modifications (PTMs) of proteins are ubiquitous processes present in all life kingdoms, involved in the regulation of protein stability, subcellular location and activity. In this context, cytochrome c (Cc) is an excellent case study to analyze the structural and functional changes induced by PTMS as Cc is a small, moonlighting protein playing different roles in different cell compartments at different cell-cycle stages. Cc is actually a key component of the mitochondrial electron transport chain (ETC) under homeostatic conditions but is translocated to the cytoplasm and even the nucleus under apoptotic conditions and/or DNA damage. Phosphorylation does specifically alter the Cc redox activity in the mitochondria and the Cc non-redox interaction with apoptosis-related targets in the cytoplasm. However, little is known on how phosphorylation alters the interaction of Cc with histone chaperones in the nucleus. Here, we report the effect of Cc Tyr48 phosphorylation by examining the protein interaction with SET/TAF-Iβ in the nuclear compartment using a combination of molecular dynamics simulations, biophysical and structural approaches such as isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) and in cell proximity ligation assays. From these experiments, we infer that Tyr48 phosphorylation allows a fine-tuning of the Cc-mediated inhibition of SET/TAF-Iβ histone chaperone activity in vitro. Our findings likewise reveal that phosphorylation impacts the nuclear, stress-responsive functions of Cc, and provide an experimental framework to explore novel aspects of Cc post-translational regulation in the nucleus.
© 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.

Accumulating evidence suggests that the nuclear envelope (NE) is not just a target, but also a mediator of apoptosis. We showed recently that the NE protein nesprin-2 has pro-apoptotic activity, which involves its subcellular redistribution and Bcl-2 proteins. Here we further characterize the pro-apoptotic activity of nesprin-2 focusing on its redistribution. We assessed the redistribution kinetics of endogenous nesprin-2 tagged with GFP relative to apoptosis-associated mitochondrial dysfunction. The results show apoptosis-induced GFP-nesprin-2G redistribution occurred by two different modes - complete and partial, both lead to appearance of nesprin-2G near the mitochondria. Moreover, GFP-nesprin-2 redistribution is associated with reduction in mitochondrial membrane potential and mitochondrial outer membrane permeabilization and precedes the appearance of morphological features of apoptosis. Our results show that nesprin-2G redistribution and translocation near mitochondria is an early apoptotic effect associated with mitochondrial dysfunction, which may be responsible for the pro-apoptotic function of nesprin-2.