Hepatic encephalopathy changes mitochondrial dynamics and autophagy in the substantia nigra
Hepatic encephalopathy (HE) has been reported in more than 40% of patients with cirrhosis in clinical practice. HE changes mitochondrial dysfunction. Mitochondrial dynamics and autophagy are important for maintaining and removing damaged mitochondria. We used molecular biology and morphology methods to evaluate changes in mitochondrial dynamics and autophagy of the substantia nigra (SN) and prefrontal cortex (PFC) in HE. In this study, we observed that HE increased mitochondrial dynamics and autophagy in the SN, which was not seen in the PFC. HE stimulated dynamin-related protein 1 (DRP1) transformation from the cytosolic to the mitochondria within SN cells, which increased mitochondrial fission and the number of mitochondria. The fusion protein L-OPA1 (long isoforms of OPA1) was increased in the SN of HE mice. HE also increased the levels of autophagy proteins PINK1/PARKIN and P62/LC3-B in the SN, which can selectively remove damaged mitochondria and cell, respectively. Additionally, we used electron microscopy to directly observe changes in mitochondrial morphology in the SN of HE mice and found the number of mitochondria was increased. However, there were no significant changes in the fission, fusion or autophagy proteins in PFC-purified mitochondrial proteins in HE mice. The number of mitochondria also did not show alterations in the PFC of HE mice compared with that in a sham group. These results illustrate that mitochondria can protect themselves by changing the dynamics and autophagy in the SN of HE mice. Changes in the mitochondrial dynamics and autophagy related to HE can help repair damaged mitochondria and provide a further understanding of the mechanisms of hepatic encephalopathy.
KeywordsHepatic encephalopathy Mitochondria Dynamics Autophagy Substantia nigra Prefrontal cortex
We would like to thank all staff members from the Department of Anatomy at the Fourth Military Medical University of China for their help with this work.
National Natural Science Foundation of China (NSFC); Grant number: 81470843.
Compliance with ethical standards
Conflict of interest
- Boer LA, Panatto JP, Fagundes DA, Bassani C, Jeremias IC, Daufenbach JF, Rezin GT, Constantino L, Dal-Pizzol F, Streck EL (2009) Inhibition of mitochondrial respiratory chain in the brain of rats after hepatic failure induced by carbon tetrachloride is reversed by antioxidants. Brain Res Bull 80(1–2):75–78CrossRefPubMedGoogle Scholar
- C.H. Chou, C.C. Lin, M.C. Yang, C.C. Wei, H.D. Liao, R.C. Lin, W.Y. Tu, T.C. Kao, C.M. Hsu, J.T. Cheng, A.K. Chou, C.I. Lee, J.K. Loh, S.L. Howng, Y.R. Hong (2012) GSK3beta-mediated Drp1 phosphorylation induced elongated mitochondrial morphology against oxidative stress. PLoS One, 7(11): Article e49112Google Scholar
- Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, Baba M, Baehrecke EH, Bahr BA, Ballabio A, Bamber BA, Bassham DC, Bergamini E, Bi X, Biard-Piechaczyk M, Blum JS, Bredesen DE, Brodsky JL, Brumell JH, Brunk UT, Bursch W, Camougrand N, Cebollero E, Cecconi F, Chen Y, Chin LS, Choi A, Chu CT, Chung J, Clark RSB, Clarke PGH, Clarke SG, Clave C, Cleveland JL, Codogno P, Colombo MI, Coto-Montes A, Cregg JM, Cuervo AM, Debnath J, Dennis PB, Dennis PA, Demarchi F, Deretic V, Devenish RJ, di Sano F, Dice JF, Distelhorst CW, Dinesh-Kumar SP, Eissa NT, DiFiglia M, Djavaheri-Mergny M, Dorsey FC, Dröge W, Dron M, Dunn WA Jr, Duszenko M, Elazar Z, Esclatine A, Eskelinen EL, Fésüs L, Finley KD, Fuentes JM, Fueyo-Margareto J, Fujisaki K, Galliot B, Gao FB, Gewirtz DA, Gibson SB, Gohla A, Goldberg AL, Gonzalez R, González-Estévez C, Gorski SM, Gottlieb RA, Häussinger D, He YW, Heidenreich K, Hill JA, Høyer-Hansen M, Hu X, Huang WP, Iwasaki A, Jäättelä M, Jackson WT, Jiang X, Jin SV, Johansen T, Jung JU, Kadowaki M, Kang C, Kelekar A, Kessel DH, Kiel JAKW, Kim HP, Kimchi A, Kinsella TJ, Kiselyov K, Kitamoto K, Knecht E, Komatsu M, Kominami E, Kondo S, Kovács AL, Kroemer G, Kuan CY, Kumar R, Kundu M, Landry J, Laporte M, le W, Lei HY, Levine B, Lieberman AP, Lim KL, Lin FC, Liou W, Liu LF, Lopez-Berestein G, López-Otín C, Lu B, Macleod KF, Malorni W, Martinet W, Matsuoka K, Mautner J, Meijer AJ, Meléndez A, Michels P, Miotto G, Mistiaen WP, Mizushima N, Mograbi B, Moore MN, Moreira PI, Moriyasu Y, Motyl T, Münz C, Murphy LO, Naqvi NI, Neufeld TP, Nishino I, Nixon RA, Noda T, Nürnberg B, Ogawa M, Oleinick NL, Olsen LJ, Ozpolat B, Paglin S, Palmer GE, Papassideri IS, Parkes M, Perlmutter DH, Perry G, Piacentini M, Pinkas-Kramarski R, Prescott M, Proikas-Cezanne T, Raben N, Rami A, Reggiori F, Rohrer B, Rubinsztein DC, Ryan KM, Sadoshima J, Sakagami H, Sakai Y, Sandri M, Sasakawa C, Sass M, Schneider C, Seglen PO, Seleverstov O, Settleman J, Shacka JJ, Shapiro IM, Sibirny AA, Silva-Zacarin ECM, Simon HU, Simone C, Simonsen A, Smith MA, Spanel-Borowski K, Srinivas V, Steeves M, Stenmark H, Stromhaug PE, Subauste CS, Sugimoto S, Sulzer D, Suzuki T, Swanson MS, Tabas I, Takeshita F, Talbot NJ, Tallóczy Z, Tanaka K, Tanaka K, Tanida I, Taylor GS, Taylor JP, Terman A, Tettamanti G, Thompson CB, Thumm M, Tolkovsky AM, Tooze SA, Truant R, Tumanovska LV, Uchiyama Y, Ueno T, Uzcátegui NL, van der Klei IJ, Vaquero EC, Vellai T, Vogel MW, Wang HG, Webster P, Xi Z, Xiao G, Yahalom J, Yang JM, Yap GS, Yin XM, Yoshimori T, Yue Z, Yuzaki M, Zabirnyk O, Zheng X, Zhu X, Deter RL (2008) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4:151–175CrossRefPubMedGoogle Scholar
- Norris KL, Hao R, Chen LF, Lai CH, Kapur M, Shaughnessy PJ, Chou D, Yan J, Taylor JP, Engelender S, West AE, Lim KL, Yao TP (2015) Convergence of Parkin, PINK1, and alpha-Synuclein on stress-induced mitochondrial morphological remodeling. J Biol Chem 290(22):13862–13874CrossRefPubMedPubMedCentralGoogle Scholar
- Rama RK, Jayakumar AR, Norenberg MD (2005) Role of oxidative stress in the ammonia-induced mitochondrial permeability transition in cultured astrocytes. Neurochem Int 47(1–2):31–38Google Scholar