Systematic review of cognitive deficits in adult mitochondrial disease

The profile and trajectory of cognitive impairment in mitochondrial disease are poorly defined. This systematic review sought to evaluate the current literature on cognition in mitochondrial disease, and to determine future research directions. A systematic review was conducted, employing PubMed, Medline, Psycinfo, Embase and Web of Science, and 360‐degree citation methods. English language papers on adult patients were included. The literature search yielded 2421 articles, of which 167 met inclusion criteria. Case reports and reviews of medical reports of patients yielded broad diagnoses of dementia, cognitive impairment and cognitive decline. In contrast, systematic investigations of cognitive functioning using detailed cognitive batteries identified focal cognitive rather than global deficits. Results were variable, but included visuospatial functioning, memory, attention, processing speed and executive functions. Conclusions from studies have been hampered by small sample sizes, variation in genotype and the breadth and depth of assessments undertaken. Comprehensive cognitive research with concurrent functional neuroimaging and physical correlates of mitochondrial disease in larger samples of well‐characterized patients may discern the aetiology and progression of cognitive deficits. These data provide insights into the pattern and trajectory of cognitive impairments, which are invaluable for clinical monitoring, health planning and clinical trial readiness.     

Interplay of metabolizing enzymes and transporter of xenobiotics

1.?Xenobiotics are metabolized and eliminated through the coordinated interplay of their metabolizing enzymes and transporters. However, these two activities in vitro are measured separately, with the addition of ATP as a pre-requisite.

2.?We propose a human renal cell-line model which integrates the sulfate and glutathione conjugation of xenobiotics with the efflux of their respective conjugates. Sulfation and glutathionylation represent two major Phase II detoxification of xenobiotics in man. The reactions are catalyzed, respectively, by phenolsulfotransferase and glutathione-S-transferase followed by extrusion of their respective conjugates.

3.?Using Ko-143, a specific inhibitor of breast cancer resistance protein (BCRP), an ATP-binding cassette (ABC) transporter, we identified this transporter to be responsible for the efflux of p-cresol sulfate, harmol sulfate and the glutathione conjugate of 1-chloro-2,4-dinitrobenzene.

4.?The conjugation-cum-efflux was inhibited by oligomycin and uncouplers, which highlights the role of cellular mitochondria in providing ATP for the biosynthesis of their conjugating agents, 3′-phosphoadenosine-5′-phosphosulfate (PAPS) and reduced glutathione as well as for the transport function of BCRP.

5.?The human 786-O renal cell-line provides a “3-in-1” system linking ATP biosynthesis to metabolism of xenobiotics and their ultimate transport and elimination by BCRP; this integrated system was not apparent in other human cell-lines examined.     

Advanced glycation end products‐induced chondrocyte apoptosis through mitochondrial dysfunction in cultured rabbit chondrocyte

Advanced glycation end products (AGEs) are an important mediator in osteoarthritis (OA) and cause apoptosis in articular chondrocytes. Mitochondrial function is involved in modulating apoptosis of articular chondrocytes. This study was performed to investigate the mechanism of AGEs‐induced chondrocyte apoptosis. The ratio of apoptotic cell and cell viability was surveyed by TUNEL, MTT,LDH release assay. The reactive oxygen species was determined by the fluorescent probe 2’, 7’‐dichlorofluorescein diacetate. The expression of caspase‐3 and cytochrome c was detected by Western blot. The mitochondrial membrane potential (?Ψm) was evaluated by rhodamine‐123 fluorescence. We found that AGEs induced apoptosis in primary rabbit chondrocytes, upregulation of ROS production, cytochrome c, and caspase‐3 levels. Simultaneously, AGEs decreases the levels of ?Ψm and ATP production; however, the antibody of AGEs (sRAGE) and antioxidant‐N‐acetylcys‐teine (NAC) significantly reversed AGEs‐induced the above damage thus to protect the cells from apoptosis. These observations suggested that the mechanism of AGEs‐induced chondrocyte apoptosis was primarily via ROS production and mitochondria‐mediated caspase‐3 activation.     

Melanoma differentiation‐associated gene 5 in zebrafish provoking higher interferon‐promoter activity through signalling enhancing of its shorter splicing variant

Melanoma differentiation‐associated gene 5 (MDA5) is one of the three members in the retinoic acid‐inducible gene I‐like receptor (RLR) family, which are cytoplasmic pathogen recognition receptors recognizing intracellular viruses. In the present study, MDA5 and its spliced shorter forms, named as MDA5a and MDA5b, were identified in zebrafish. MDA5a and MDA5b can be up‐regulated in cell lines following the infection of a negative ssRNA virus, the spring viraemia of carp virus (SVCV), and an intracellular Gram‐negative bacterial pathogen Edwardsiella tarda, implying that the RLR may also be able to sense elements released from bacteria. The over‐expression of MDA5a and MDA5b in fish cells resulted in significant induction of type I interferon promoter activity and enabled the protection of transfected cells against SVCV infection. Furthermore, the shorter spliced form, MDA5b when co‐transfected with MDA5a or mitochondrial antiviral signalling protein (MAVS), induced a significantly higher level of interferon promoter activity, indicating that MDA5b may function as an enhancer in the interaction between MDA5 and MAVS.     

Empagliflozin restores chronic kidney disease–induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction

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Mitochondrial compromise in 3‐year old patas monkeys exposed in utero to human‐equivalent antiretroviral therapies

Antiretroviral (ARV) drug therapy, given during pregnancy for prevention of mother‐to‐child transmission of human immunodeficiency virus 1 (HIV‐1), induces fetal mitochondrial dysfunction in some children. However, the persistence/reversibility of that dysfunction is unclear. Here we have followed Erythrocebus patas (patas) monkey offspring for up to 3 years of age (similar in development to a 15‐year old human) after exposure of the dams to human‐equivalent in utero ARV exposure protocols. Pregnant patas dams (3–5/exposure group) were given ARV drug combinations that included zidovudine (AZT)/lamivudine (3TC)/abacavir (ABC), or AZT/3TC/nevirapine (NVP), for the last 10 weeks (50%) of gestation. Infants kept for 1 and 3 years also received drug for the first 6 weeks of life. In offpsring at birth, 1 and 3 years of age mitochondrial morphology, examined by electron microscopy (EM), was compromised compared to the unexposed controls. Mitochondrial DNA (mtDNA), measured by hybrid capture chemiluminescence assay (HCCA) was depleted in hearts of patas exposed to AZT/3TC/NVP at all ages (P < 0.05), but not in those exposed to AZT/3TC/ABC at any age. Compared to unexposed controls, mitochondrial reserve capacity oxygen consumption rate (OCR by Seahorse) in cultured bone marrow mesenchymal fibroblasts from 3‐year‐old patas offspring was ～50% reduced in AZT/3TC/ABC‐exposed patas (P < 0.01), but not in AZT/3TC/NVP‐exposed patas. Overall the data show that 3‐year‐old patas sustain persistent mitochondrial dysfunction as a result of perinatal ARV drug exposure. Environ. Mol. Mutagen. 57:526–534, 2016. © 2016 Wiley Periodicals, Inc.