Erythrocytes ; metabolism ; Humans ; Kidney Diseases ; genetics ; metabolism ; Mitochondria ; genetics ; Mitochondrial Membranes ; metabolism ; Oxidative Stress ; genetics ; physiology

Zn²⁺ is required for the activity of many mitochondrial proteins, which regulate mitochondrial dynamics, apoptosis and mitophagy. However, it is not understood how the proper mitochondrial Zn²⁺ level is achieved to maintain mitochondrial homeostasis. Using Caenorhabditis elegans, we reveal here that a pair of mitochondrion-localized transporters controls the mitochondrial level of Zn²⁺. We demonstrate that SLC-30A9/ZnT9 is a mitochondrial Zn²⁺ exporter. Loss of SLC-30A9 leads to mitochondrial Zn²⁺ accumulation, which damages mitochondria, impairs animal development and shortens the life span. We further identify SLC-25A25/SCaMC-2 as an important regulator of mitochondrial Zn²⁺ import. Loss of SLC-25A25 suppresses the abnormal mitochondrial Zn²⁺ accumulation and defective mitochondrial structure and functions caused by loss of SLC-30A9. Moreover, we reveal that the endoplasmic reticulum contains the Zn²⁺ pool from which mitochondrial Zn²⁺ is imported. These findings establish the molecular basis for controlling the correct mitochondrial Zn²⁺ levels for normal mitochondrial structure and functions.
Animals ; Caenorhabditis elegans/metabolism* ; Cation Transport Proteins/genetics* ; Homeostasis ; Mitochondria/metabolism* ; Zinc/metabolism*

Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6-CREB-SOD2-dependent pathway in IgG4-RS.
Cellular Senescence/genetics* ; Humans ; Immunoglobulin G/metabolism* ; Interleukin-13/pharmacology* ; Mitochondria/metabolism* ; Sialadenitis/metabolism*

Mitophagy is one of the important targets for the prevention and treatment of myocardial ischemia/reperfusion injury (MIRI). Moderate mitophagy can remove damaged mitochondria, inhibit excessive reactive oxygen species accumulation, and protect mitochondria from damage. However, excessive enhancement of mitophagy greatly reduces adenosine triphosphate production and energy supply for cell survival, and aggravates cell death. How dysfunctional mitochondria are selectively recognized and engulfed is related to the interaction of adaptors on the mitochondrial membrane, which mainly include phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced kinase 1/Parkin, hypoxia-inducible factor-1 α/Bcl-2 and adenovirus e1b19k Da interacting protein 3, FUN-14 domain containing protein 1 receptor-mediated mitophagy pathway and so on. In this review, the authors briefly summarize the main pathways currently studied on mitophagy and the relationship between mitophagy and MIRI, and incorporate and analyze research data on prevention and treatment of MIRI with Chinese medicine, thereby provide relevant theoretical basis and treatment ideas for clinical prevention of MIRI.
Humans ; Mitochondria/metabolism* ; Mitophagy/genetics* ; Myocardial Reperfusion Injury ; Protein Kinases/metabolism*

Tumorigenesis is a complex process that is regulated by a variety of network signals. With the continuous development of the process, tumor cells gradually exhibit lots of hallmarks.Tumor cells have the characteristics of unlimited proliferation, resistance to apoptosis, evading immune surveillance, among others. As a unique organelles, mitochondria play an important role in cellular energy metabolism, reactive oxygen species producing and apoptosis process. Particularly, mitochondria have a close relationship with tumor development. In this review, we focus on the essential role of mitochondria in tumor cells development.
Animals ; Energy Metabolism ; Humans ; Mitochondria ; metabolism ; physiology ; Neoplasms ; etiology ; genetics ; physiopathology ; Tumor Microenvironment ; physiology

OBJECTIVETo investigate the abundance of metabolic proteins in adult and fetal human livers.

METHODSAdult liver homogenate proteins, fetal liver homogenate proteins, adult liver mitochondrial proteins and fetal liver mitochondrial proteins were obtained from fetal or adult liver tissues and examined using the antibody microarrays containing 19 liver monoclonal mitochondrial antibodies. The protein expression abundances were compared among the 4 protein fractions and the pathways related to protein metabolisms were explored.

RESULTSIn adult liver mitochondria, aldehyde oxidase and carbonyl reductase were up-regulated by 2.6 and 1.7 folds, respectively, whereas corticosteroid 11-beta-dehydrogenase isozyme 1, epoxide hydrolase 1 and fibrinogen beta chain protein were down-regulated by 1.7, 1.9 and 2.2 folds, respectively, compared to those in fetal liver mitochondria. The abundance of epoxide hydrolase 1 and glutathione transferase omega-1 was significantly different between adult and fetal liver homogenate samples.

CONCLUSIONOur results demonstrate a clear difference in the expression profiles of metabolic proteins in the liver between adults and human fetuses to allow a better understanding of the occurrence and development of the metabolic proteins and the identification of markers of liver metabolism.

Adult ; Antibodies ; genetics ; metabolism ; Fetus ; metabolism ; Humans ; Liver ; embryology ; metabolism ; Mitochondria, Liver ; metabolism ; Mitochondrial Proteins ; metabolism ; Protein Array Analysis

The human mitochondrial genome consists of approximate 1500 genes, among which 37 are encoded by the mitochondrial DNA (mtDNA) and the remainder encoded in the nuclear DNA (nDNA). The mitochondria produces large amount of the cellular reactive oxygen species (ROS). ROS induces the mutations of mtDNA and mtDNA, which are associated with a wide range of age-related diseases including neurodegenerative diseases, cardiomyopathy, diabetes and various cancers.
Aging ; DNA, Mitochondrial ; genetics ; Genetic Therapy ; Humans ; Mitochondria ; genetics ; metabolism ; Mutation ; Neurodegenerative Diseases ; genetics ; therapy ; Reactive Oxygen Species ; metabolism

Apoptosis ; Down-Regulation ; Electron Transport Complex IV ; chemistry ; genetics ; metabolism ; Humans ; Mitochondria ; metabolism ; Mutation ; Neoplasms ; genetics ; metabolism ; pathology

OBJECTIVETo explore the subcellular localization of ataxin-3 and the effect of polyglutamine (polyQ) expansion mutation on the morphology of mitochondrion, golgi apparatus and endoplasmic reticulum.

METHODSTransient transfection was employed to build cell models expressing wild-type or mutant ataxin-3 proteins. Indirect immunofluorescence was applied to identify markers of organelle membrane. The results were observed under a laser scanning confocal microscope.

RESULTSNo co-localization was observed for ataxin-3 protein and mitochondrial marker TOM20, but the percentage of cells with mitochondrial fragmentation has increased in cells expressing mutant ataxin-3 (P<0.05). No co-localization was observed for ataxin-3 protein and golgi marker GM130, and mutant ataxin-3 did not cause golgi fragmentation. Wide type and polyQ-expanded ataxin-3 both showed partial co-localization with ER marker calnexin. The latter showed more overlap with calnexin, and the overlapping signals were mostly located in the places where aggregates were situated.

CONCLUSIONPolyQ-expanded ataxin-3 protein may indirectly affect the integrity of mitochondria, but may cause no effect on the structure and functions of golgi apparatus. Endoplasmic reticulum may be another place where extended ataxin-3 protein can induce cytotoxicity in addition to the nucleus.

Ataxin-3 ; Cytoplasm ; genetics ; metabolism ; Endoplasmic Reticulum ; genetics ; metabolism ; HeLa Cells ; Humans ; Machado-Joseph Disease ; genetics ; metabolism ; Mitochondria ; genetics ; metabolism ; Nerve Tissue Proteins ; genetics ; metabolism ; Nuclear Proteins ; genetics ; metabolism ; Protein Transport ; Repressor Proteins ; genetics ; metabolism

Animals ; Gene Expression Profiling ; Mitochondria, Heart ; genetics ; metabolism ; Myocardial Reperfusion Injury ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley