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Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how UPRmt regulators are orchestrated to transcriptionally activate stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator of the UPRmt, as well as mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300. more...

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation– and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle. more...

Reticular Dysgenesis is a particularly grave form of severe combined immunodeficiency (SCID) because it affects the adaptive and innate immune system. Patients suffer from congenital neutropenia, defective lymphocyte development and sensorineural hearing loss. The disease is caused by biallelic loss of function mutations in the mitochondrial enzyme Adenylate Kinase 2 (AK2). AK2 mediates the phosphorylation of adenosine monophosphate (AMP) to adenosine diphosphate (ADP) as substrate for adenosine triphosphate (ATP) synthesis. Accordingly, declining OXPHOS metabolism has been postulated as the driver of disease pathology. The mechanistic basis for the failure of myelopoiesis and lymphopoiesis in Reticular Dysgenesis, however, remains incompletely understood. We have used single cell RNA-sequencing of bone marrow cells from two Reticular Dysgenesis patients to gain insight into the disease mechanism. Gene set enrichment analysis of differentially expressed genes in different subsets of myeloid and lymphoid progenitor cells implicated processes involved in RNA catabolism and ribonucleoprotein synthesis in the pathogenesis of Reticular Dysgenesis. To investigate these findings and precisely mimic the failure of human myelopoiesis in culture, we developed a cell-traceable disease model for Reticular Dysgenesis based on CRISPR-mediated disruption of the AK2 gene in primary human hematopoietic stem cells. In this model, we have shown that AK2-deficienct myeloid progenitor cells not only have compromised mitochondrial energy metabolism and increased AMP levels, but also NAD+ and aspartate depletion, metabolites that rely on TCA-cycle activity for regeneration and synthesis. Furthermore, AK2-deficient cells exhibited strikingly increased levels in the purine nucleotide precursor inosine monophosphate (IMP), decreased cellular RNA content and ribosome subunit expression, reduced protein synthesis and a profoundly hypo-proliferative phenotype. Although NAD+ and aspartate are critical substrates of purine synthesis, AK2-deficient cells did not exhibit purine auxotrophy. Instead, our studies revealed that the rise in IMP levels stemmed from increased AMP deamination. Pharmacologic inhibition of AMP deaminase normalized IMP levels in AK2-deficient cells, but further aggravated the Reticular Dysgenesis phenotype, suggesting AMP catabolism to IMP represents a metabolic adaptation to mitigate AMP-mediated toxicity. This study is the first to identify globally curtailed mitochondrial metabolism resulting in NAD+ and aspartate deficiency and disordered purine metabolism as the two primary cellular consequences of AK2-deficiency. Our data suggests that AMP accumulation and its detrimental effects on ribonucleotide synthesis capacity are the dominant driver of cellular pathology causing failure of myelopoiesis in Reticular Dysgenesis. more...

Mitochondrial dysfunction is associated with aging‐mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress‐induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro‐inflammatory cytokines in elderly subjects. Circulating levels of cell‐free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20‐month‐old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15‐deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL‐17 production in Th17 cells, GDF15 contributes to regulatory T‐cell‐mediated suppression of conventional T‐cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging‐mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice., Aging‐induced GDF15 production is observed in humans and mice, which is positively correlated with systemic inflammation and mitochondrial stress. GDF15 deficiency promotes glucose intolerance as well as hepatic and adipose inflammation in old mice. GDF15 contributes to regulatory T cells‐mediated suppression of conventional T cell activation, but senescent T cells were resistant to regulatory T cells‐mediated suppression compared to conventional T cells. more...