bims-camemi 2018-09-09 papers

Free Radic Biol Med. 2018 Aug 30. pii: S0891-5849(18)31184-5. [Epub ahead of print]

AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis.

Dong Liu, Zhiqiang Ma, Shouyin Di, Yang Yang, Jingang Yang, Liqun Xu, Russel J Reiter, Shubin Qiao, Jiansong Yuan.

Doxorubicin (DOX) is a highly effective anticancer anthracycline drug, but its side effects at the level of the heart has limited its widespread clinical application. Melatonin is a documented potent antioxidant, nontoxic and cardioprotective agent, and it is involved in maintaining mitochondrial homeostasis and function. The present study established acute DOX-induced cardiotoxicity models in both H9c2 cells incubated with 1μM DOX and C57BL/6 mice treated with DOX (20mg/kg cumulative dose). Melatonin markedly alleviated the DOX-induced acute cardiac dysfunction and myocardial injury. Both in vivo and in vitro studies verified that melatonin inhibited DOX-induced mitochondrial dysfunction and morphological disorders, apoptosis, and oxidative stress via the activation of AMPK and upregulation of PGC1α with its downstream signaling (NRF1, TFAM and UCP2). These effects were reversed by the use of AMPK siRNA or PGC1α siRNA in H9c2 cells, and were also negated by the cotreatment with AMPK inhibitor Compound C in vivo. Moreover, PGC1α knockdown was without effect on the AMPK phosphorylation induced by melatonin in the DOX treated H9c2 cells. Therefore, AMPK/PGC1α pathway activation may represent a new mechanism for melatonin exerted protection against acute DOX cardiotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis.

Keywords: AMPK; Melatonin; PGC1α; apoptosis; cardiotoxicity; doxorubicin; mitochondria

DOI: https://doi.org/10.1016/j.freeradbiomed.2018.08.032

Redox Biol. 2018 Aug 24. pii: S2213-2317(18)30409-9. [Epub ahead of print]19 158-165

Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells.

Jun Yang, Zongmeng Chen, Nan Liu, Yijun Chen.

Tumorigenesis is commonly known as a complicated process, in which reactive oxygen species (ROS) plays a critical role to involve in signal transduction, metabolism, cell proliferation and differentiation. Previously, ribosomal protein L10 (RPL10) was suggested to possess extra-ribosomal functions in pancreatic cancer cells in addition to being proposed as a tumor suppressor or transcription co-regulator. To better understand the relationship between RPL10 and tumorigenic potential in pancreatic cancer cells, chromatin immunoprecipitation sequencing reveals that RPL10 is unlikely to be a transcription factor without a specific binding motif for gene transcription. Additionally, transcriptome analysis indicates that RPL10 could regulate the expression of proteins related to ROS production. Moreover, RPL10 in mitochondria is closely associated with the regulation of ROS level by affecting Complex I activity and the subsequent events. Together, the present study suggests that the regulation of ROS level by mitochondrial RPL10 is one of the major extra-ribosomal functions in pancreatic cancer cells, which could be used as an indicator for the tumorigenesis of pancreatic cancer.

Keywords: Mitochondria; Pancreatic cancer; ROS; RPL10; Regulation

DOI: https://doi.org/10.1016/j.redox.2018.08.016

J Mol Biol. 2018 Aug 29. pii: S0022-2836(18)30987-2. [Epub ahead of print]

Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with either Sporadic or Familial Alzheimer's Disease.

Simon M Bell, Katy Barnes, Hannah Clemmens, Aziza R Al-Rafiah, Ebtisam A Al-Ofi, Vicki Leech, Oliver Bandmann, Pamela J Shaw, Daniel J Blackburn, Laura Ferraiuolo, Heather Mortiboys.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Mitochondrial abnormalities have been identified in many cell types in AD, with deficits preceding the development of the classical pathological aggregations. Ursodeoxycholic acid (UDCA), a treatment for primary biliary cirrhosis, improves mitochondrial function in fibroblasts derived from Parkinson's disease (PD) patients as well as several animal models of AD and PD. In this paper, we investigated both mitochondrial function and morphology in fibroblasts from patients with both sporadic and familial AD. We show that both sporadic AD (sAD) and PSEN1 fibroblasts share the same impairment of mitochondrial membrane potential and alterations in mitochondrial morphology. Mitochondrial respiration, however, was decreased in sAD fibroblasts and increased in PSEN1 fibroblasts. Morphological changes seen in AD fibroblasts include reduced mitochondrial number and increased mitochondrial clustering around the cell nucleus as well as an increased number of long mitochondria. We show here for the first time in AD patient tissue that treatment with UDCA increases mitochondrial membrane potential and respiration as well as reducing the amount of long mitochondria in AD fibroblasts. In addition we show reductions in Dynamin-related protein 1 (Drp1) level; particularly the amount localised to mitochondria in both sporadic AD and familial patient fibroblasts. Drp1 protein amount and localization were increased after UDCA treatment. The restorative effects of UDCA are abolished when Drp1 is knocked down. This paper highlights the potential use of UDCA as a treatment for neurodegenerative disease.

Keywords: Mitochondrial morphology; Neurodegeneration; Presenilin; Treatment; UDCA

DOI: https://doi.org/10.1016/j.jmb.2018.08.019

Free Radic Biol Med. 2018 Aug 30. pii: S0891-5849(18)30974-2. [Epub ahead of print]

Mitochondrial calcium transport and the redox nature of the calcium-induced membrane permeability transition.

Anibal E Vercesi, Roger F Castilho, Alicia J Kowaltowski, Helena C F de Oliveira, Nadja C de Souza-Pinto, Tiago R Figueira, Estela N B Busanello.

Mitochondria possess a Ca2+ transport system composed of separate Ca2+ influx and efflux pathways. Intramitochondrial Ca2+ concentrations regulate oxidative phosphorylation, required for cell function and survival, and mitochondrial redox balance, that participates in a myriad of signaling and damaging pathways. The interaction between Ca2+ accumulation and redox imbalance regulates opening and closing of a highly regulated inner membrane pore, the membrane permeability transition pore (PTP). In this review, we discuss the regulation of the PTP by mitochondrial oxidants, reactive nitrogen species, and the interactions between these species and other PTP inducers. In addition, we discuss the involvement of mitochondrial redox imbalance and PTP in metabolic conditions such as atherogenesis, diabetes, obesity and in mtDNA stability.

DOI: https://doi.org/10.1016/j.freeradbiomed.2018.08.034

Biochem Pharmacol. 2018 Aug 30. pii: S0006-2952(18)30370-8. [Epub ahead of print]

Operation of mitochondrial machinery in viral infection-induced immune responses.

Jenn-Haung Lai, Shue-Fen Luo, Ling-Jun Ho.

Mitochondria have been recognized as ancient bacteria that contain evolutionary endosymbionts. Metabolic pathways and inflammatory signals interact within mitochondria in response to different stresses, such as viral infections. In this commentary, we address several interesting questions, including (1) how do mitochondrial machineries participate in immune responses; (2) how do mitochondria mediate antiviral immunity; (3) what mechanisms involved in mitochondrial machinery, including the downregulation of mitochondrial DNA (mtDNA), disturbances of mitochondrial dynamics, and the induction of mitophagy and regulation of apoptosis, have been adopted by viruses to evade antiviral immunity; (4) what mechanisms involve the regulation of mitochondrial machineries in antiviral therapeutics; and (5) what are the potential challenges and perspectives in developing mitochondria-targeting antiviral treatments? This commentary provides a comprehensive review of the roles and mechanisms of mitochondrial machineries in immunity, viral infections and related antiviral therapeutics.

Keywords: Immune; Mitochondria; Therapy; Virus

DOI: https://doi.org/10.1016/j.bcp.2018.08.044