NADH dehydrogenase 5 (ND5) is one of 44 subunits composed of Complex I in mitochondrial respiratory chain. Therefore, a mitochondrially encoded ND5 (MT-ND5) gene mutation causes mitochondrial oxidative phosphorylation (OXPHOS) disorder, resulting in the development of mitochondrial diseases. Focal segmental glomerulosclerosis (FSGS) which had podocytes filled with abnormal mitochondria is induced by mitochondrial diseases. An MT-ND5 mutation also causes FSGS. We herein report a Japanese woman who was found to have proteinuria and renal dysfunction in an annual health check-up at 29 years old. Because her proteinuria and renal dysfunction were persistent, she had a kidney biopsy at 33 years of age. The renal histology showed FSGS with podocytes filled with abnormal mitochondria. The podocytes also had foot process effacement and cytoplasmic vacuolization. In addition, the renal pathological findings showed granular swollen epithelial cells (GSECs) in tubular cells, age-inappropriately disarranged and irregularly sized vascular smooth muscle cells (AiDIVs), and red-coloured podocytes (ReCPos) by acidic dye. A genetic analysis using peripheral mononuclear blood cells and urine sediment cells detected the m.13513 G > A variant in the MT-ND5 gene. Therefore, this patient was diagnosed with FSGS due to an MT-ND5 gene mutation. Although this is not the first case report to show that an MT-ND5 gene mutation causes FSGS, this is the first to demonstrate podocyte injuries accompanied with accumulation of abnormal mitochondria in the cytoplasm.

Mitochondrial abnormalities have long been described in the setting of cardiomyopathies and heart failure (HF), yet the mechanisms of mitochondrial dysfunction in cardiac pathophysiology remain poorly understood. Many studies have described HF as an energy-deprived state characterized by a decline in adenosine triphosphate production, largely driven by impaired oxidative phosphorylation. However, impairments in oxidative phosphorylation extend beyond a simple decline in adenosine triphosphate production and, in fact, reflect pervasive metabolic aberrations that cannot be fully appreciated from the isolated, often siloed, interrogation of individual aspects of mitochondrial function. With the application of broader and deeper examinations into mitochondrial and metabolic systems, recent data suggest that HF with preserved ejection fraction is likely metabolically disparate from HF with reduced ejection fraction. In our review, we introduce the concept of the mitochondrial ecosystem, comprising intricate systems of metabolic pathways and dynamic changes in mitochondrial networks and subcellular locations. The mitochondrial ecosystem exists in a delicate balance, and perturbations in one component often have a ripple effect, influencing both upstream and downstream cellular pathways with effects enhanced by mitochondrial genetic variation. Expanding and deepening our vantage of the mitochondrial ecosystem in HF is critical to identifying consistent metabolic perturbations to develop therapeutics aimed at preventing and improving outcomes in HF.

UNASSIGNED: XBP1 modulates the macrophage proinflammatory response, but its function in macrophage stimulator of interferon genes (STING) activation and liver fibrosis is unknown. X-box binding protein 1 (XBP1) has been shown to promote macrophage nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) activation in steatohepatitis. Herein, we aimed to explore the underlying mechanism of XBP1 in the regulation of STING signalling and the subsequent NLRP3 activation during liver fibrosis.
UNASSIGNED: XBP1 expression was measured in the human fibrotic liver tissue samples. Liver fibrosis was induced in myeloid-specific Xbp1-, STING-, and Nlrp3-deficient mice by carbon tetrachloride injection, bile duct ligation, or a methionine/choline-deficient diet.
UNASSIGNED: Although increased XBP1 expression was observed in the fibrotic liver macrophages of mice and clinical patients, myeloid-specific Xbp1 deficiency or pharmacological inhibition of XBP1 protected the liver against fibrosis. Furthermore, it inhibited macrophage NLPR3 activation in a STING/IRF3-dependent manner. Oxidative mitochondrial injury facilitated cytosolic leakage of macrophage self-mtDNA and cGAS/STING/NLRP3 signalling activation to promote liver fibrosis. Mechanistically, RNA sequencing analysis indicated a decreased mtDNA expression and an increased BCL2/adenovirus E1B interacting protein 3 (BNIP3)-mediated mitophagy activation in Xbp1-deficient macrophages. Chromatin immunoprecipitation (ChIP) assays further suggested that spliced XBP1 bound directly to the Bnip3 promoter and inhibited the transcription of Bnip3 in macrophages. Xbp1 deficiency decreased the mtDNA cytosolic release and STING/NLRP3 activation by promoting BNIP3-mediated mitophagy activation in macrophages, which was abrogated by Bnip3 knockdown. Moreover, macrophage XBP1/STING signalling contributed to the activation of hepatic stellate cells.
UNASSIGNED: Our findings demonstrate that XBP1 controls macrophage cGAS/STING/NLRP3 activation by regulating macrophage self-mtDNA cytosolic leakage via BNIP3-mediated mitophagy modulation, thus providing a novel target against liver fibrosis.
UNASSIGNED: Liver fibrosis is a typical progressive process of chronic liver disease, driven by inflammatory and immune responses, and is characterised by an excess of extracellular matrix in the liver. Currently, there is no effective therapeutic strategy for the treatment of liver fibrosis, resulting in high mortality worldwide. In this study, we found that myeloid-specific Xbp1 deficiency protected the liver against fibrosis in mice, while XBP1 inhibition ameliorated liver fibrosis in mice. This study concluded that targeting XBP1 signalling in macrophages may provide a novel strategy for protecting the liver against fibrosis.

Biallelic deletions extending into the ATPase family AAA-domain containing protein 3A (ATAD3A) gene lead to infantile lethality with severe pontocerebellar hypoplasia (PCH). However, only 12 such cases have been reported worldwide to date, and the genotype-phenotype correlations are not well understood. We describe cases associated with the same novel biallelic deletions of the ATAD3A and ATAD3B/3A regions in Japanese siblings with severe spinal cord hypoplasia and multiple malformations, including PCH, leading to neonatal death. The ATAD3A protein is essential for normal interaction between mitochondria and endoplasmic reticulum and is important for mitochondrial biosynthesis. The cases were evaluated using whole-genome sequencing for genetic diagnosis of mitochondrial disease. Spinal cord lesions associated with biallelic compound heterozygous deletion extending into the ATAD3A gene have not been reported. In addition, the ATAD3A deletion was 19 base pairs long, which is short compared with those reported previously. This deletion introduced a frameshift, resulting in a premature termination codon, and was expected to be a null allele. The pathological findings of the atrophic spinal cord showed gliosis and tissue destruction of the gray and white matter. We describe spinal cord lesions as a new central nervous system phenotype associated with a biallelic compound heterozygous deletion extending into the ATAD3A gene. Biallelic ATAD3A deletions should be considered in cases of mitochondrial disease with spinal cord hypoplasia and PCH.

UNASSIGNED: High-dose irradiation is an essential tool to help control the growth of hepatic tumors, but it can cause radiation-induced liver disease (RILD). This life-threatening complication manifests itself months following radiation therapy and is characterized by fibrosis of the pericentral sinusoids. In this study, we aimed to establish a mouse model of RILD to investigate the underlying mechanism of radiation-induced liver fibrosis.
UNASSIGNED: Using a small animal image-guided radiation therapy platform, an irradiation scheme delivering 50 Gy as a single dose to a focal point in mouse livers was designed. Tissues were analyzed 1 and 6 days, and 6 and 20 weeks post-irradiation. Irradiated livers were assessed by histology, immunohistochemistry, imaging mass cytometry and RNA sequencing. Mitochondrial function was assessed using high-resolution respirometry.
UNASSIGNED: At 6 and 20 weeks post-irradiation, pericentral fibrosis was visible in highly irradiated areas together with immune cell infiltration and extravasation of red blood cells. RNA sequencing analysis showed gene signatures associated with acute DNA damage, p53 activation, senescence and its associated secretory phenotype and fibrosis. Moreover, gene profiles of mitochondrial damage and an increase in mitochondrial DNA heteroplasmy were detected. Respirometry measurements of hepatocytes in vitro confirmed irradiation-induced mitochondrial dysfunction. Finally, the highly irradiated fibrotic areas showed markers of reactive oxygen species such as decreased glutathione and increased lipid peroxides and a senescence-like phenotype.
UNASSIGNED: Based on our mouse model of RILD, we propose that irradiation-induced mitochondrial DNA instability contributes to the development of fibrosis via the generation of excessive reactive oxygen species, p53 pathway activation and a senescence-like phenotype.
UNASSIGNED: Irradiation is an efficient cancer therapy, however, its applicability to the liver is limited by life-threatening radiation-induced hepatic fibrosis. We have developed a new mouse model of radiation-induced liver fibrosis, that recapitulates the human disease. Our model highlights the role of mitochondrial DNA instability in the development of irradiation-induced liver fibrosis. This new model and subsequent findings will help increase our understanding of the hepatic reaction to irradiation and to find strategies that protect the liver, enabling the expanded use of radiotherapy to treat hepatic tumors.

Aging is by far the most prominent risk factor for Alzheimer\'s disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.

Alzheimer\'s disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.

Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial-mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy.

Pyroptosis is the process of inflammatory cell death. The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection. Excessive pyroptosis, however, leads to several inflammatory diseases, including sepsis and autoimmune disorders. Pyroptosis can be canonical or noncanonical. Upon microbe infection, the canonical pathway responds to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), while the noncanonical pathway responds to intracellular lipopolysaccharides (LPS) of Gram-negative bacteria. The last step of pyroptosis requires the cleavage of gasdermin D (GsdmD) at D275 (numbering after human GSDMD) into N- and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11 (caspase 4/5 in humans, caspase 11 in mice) in the noncanonical pathway. Upon cleavage, the N-terminus of GsdmD (GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1β and IL-18 and disturbs the regulation of ions and water, eventually resulting in strong inflammation and cell death. Since GsdmD is the effector of pyroptosis, promising inhibitors of GsdmD have been developed for inflammatory diseases. This review will focus on the roles of GsdmD during pyroptosis and in diseases.