Skip to main content
SpringerLink
Log in

Hepatic encephalopathy changes mitochondrial dynamics and autophagy in the substantia nigra

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Aldridge DR, Tranah EJ, Shawcross DL (2015) Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. J Clin Exp Hepatol 5(Suppl 1):S7–S20

    Article  PubMed  Google Scholar 

  • Alvarez VM, Rama RK, Brahmbhatt M, Norenberg MD (2011) Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. J Neurosci Res 89(12):2028–2040

    Article  CAS  PubMed  Google Scholar 

  • 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):75–78

    Article  CAS  PubMed  Google Scholar 

  • Brusilow SW, Koehler RC, Traystman RJ, Cooper AJ (2010) Astrocyte glutamine synthetase: importance in hyperammonemic syndromes and potential target for therapy. Neurotherapeutics 7(4):452–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buhlman L, Damiano M, Bertolin G, Ferrando-Miguel R, Lombes A, Brice A, Corti O (2014) Functional interplay between Parkin and Drp1 in mitochondrial fission and clearance. Biochim Biophys Acta 1843(9):2012–2026

    Article  CAS  PubMed  Google Scholar 

  • Bustamante J, Lores-Arnaiz S, Tallis S, Rosello DM, Lago N, Lemberg A, Boveris A, Perazzo JC (2011) Mitochondrial dysfunction as a mediator of hippocampal apoptosis in a model of hepatic encephalopathy. Mol Cell Biochem 354(1–2):231–240

    Article  CAS  PubMed  Google Scholar 

  • Bustos G, Cruz P, Lovy A, Cardenas C (2017) Endoplasmic reticulum-mitochondria calcium communication and the regulation of mitochondrial metabolism in Cancer: a novel potential target. Front Oncol 7:199

    Article  PubMed  PubMed Central  Google Scholar 

  • Butterworth RF (2016) Neurosteroids in hepatic encephalopathy: novel insights and new therapeutic opportunities. J Steroid Biochem Mol Biol 160:94–97

    Article  CAS  PubMed  Google Scholar 

  • Cauli O, Llansola M, Erceg S, Felipo V (2006) Hypolocomotion in rats with chronic liver failure is due to increased glutamate and activation of metabotropic glutamate receptors in substantia nigra. J Hepatol 45(5):654–661

    Article  CAS  PubMed  Google 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 e49112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cooper AJ, Lai JC (1987) Cerebral ammonia metabolism in normal and hyperammonemic rats. Neurochem Pathol 6(1–2):67–95

    Article  CAS  PubMed  Google Scholar 

  • Dhanda S, Sunkaria A, Halder A, Sandhir R (2018) Mitochondrial dysfunctions contribute to energy deficits in rodent model of hepatic encephalopathy. Metab Brain Dis 33(1):209–223

    Article  CAS  PubMed  Google Scholar 

  • Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 19(24):4861–4870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giewekemeyer K, Berding G, Ahl B, Ennen JC, Weissenborn K (2007) Bradykinesia in cirrhotic patients with early hepatic encephalopathy is related to a decreased glucose uptake of frontomesial cortical areas relevant for movement initiation. J Hepatol 46(6):1034–1039

    Article  CAS  PubMed  Google Scholar 

  • Guillery O, Malka F, Landes T, Guillou E, Blackstone C, Lombès A, Belenguer P, Arnoult D, Rojo M (2008) Metalloprotease-mediated OPA1 processing is modulated by the mitochondrial membrane potential. Biol Cell 100(5):315–325

    Article  CAS  PubMed  Google Scholar 

  • Guo K, Lu J (2015) Protective role of PGC-1alpha in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling. PLoS One 10(4):e0125176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imai Y, Lu B (2011) Mitochondrial dynamics and mitophagy in Parkinson's disease: disordered cellular power plant becomes a big deal in a major movement disorder. Curr Opin Neurobiol 21(6):935–941

    Article  CAS  PubMed  PubMed Central  Google 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 4:151–175

    Article  CAS  PubMed  Google Scholar 

  • Leboucher GP, Tsai YC, Yang M, Shaw KC, Zhou M, Veenstra TD, Glickman MH, Weissman AM (2012) Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Mol Cell 47(4):547–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee S, Zhang C, Liu X (2015) Role of glucose metabolism and ATP in maintaining PINK1 levels during Parkin-mediated mitochondrial damage responses. J Biol Chem 290(2):904–917

    Article  CAS  PubMed  Google Scholar 

  • Li S, Wang J, Zhou A, Khan FA, Hu L, Zhang S (2016) Porcine reproductive and respiratory syndrome virus triggers mitochondrial fission and mitophagy to attenuate apoptosis. Oncotarget 7(35):56002–56012

    PubMed  PubMed Central  Google Scholar 

  • Liere V, Sandhu G, DeMorrow S (2017) Recent advances in hepatic encephalopathy. F1000Res 6:1637

    Article  PubMed  PubMed Central  Google Scholar 

  • Norenberg MD, Rao KV (2007) The mitochondrial permeability transition in neurologic disease. Neurochem Int 50(7–8):983–997

    Article  CAS  PubMed  PubMed Central  Google 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):13862–13874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otera H, Ishihara N, Mihara K (2013) New insights into the function and regulation of mitochondrial fission. Biochim Biophys Acta 1833(5):1256–1268

    Article  CAS  PubMed  Google Scholar 

  • Rama RK, Norenberg MD (2012) Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy. Neurochem Int 60(7):697–706

    Article  CAS  Google Scholar 

  • Rama RK, Jayakumar AR, Norenberg DM (2003) Ammonia neurotoxicity: role of the mitochondrial permeability transition. Metab Brain Dis 18(2):113–127

    Article  Google 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):31–38

    Google Scholar 

  • Rao KV, Norenberg MD (2001) Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia. Metab Brain Dis 16(1–2):67–78

    Article  CAS  PubMed  Google Scholar 

  • Rusten TE, Stenmark H (2010) p62, an autophagy hero or culprit? Nat Cell Biol 12(3):207–209

    Article  CAS  PubMed  Google Scholar 

  • Ruszkiewicz J, Albrecht J (2015) Changes in the mitochondrial antioxidant systems in neurodegenerative diseases and acute brain disorders. Neurochem Int 88:66–72

    Article  CAS  PubMed  Google Scholar 

  • Vigie P, Camougrand N (2017) Role of mitophagy in the mitochondrial quality control. Med Sci (Paris) 33(3):231–237

    Article  Google Scholar 

  • Vives-Bauza C, Przedborski S (2011) Mitophagy: the latest problem for Parkinson's disease. Trends Mol Med 17(3):158–165

    Article  CAS  PubMed  Google Scholar 

  • Yang YL, Li JJ, Ji R, Wei YY, Chen J, Dou KF, Wang YY (2013) Abnormal chloride homeostasis in the substancia nigra pars reticulata contributes to locomotor deficiency in a model of acute liver injury. PLoS One 8(5):e65194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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.

Grant sponsor

National Natural Science Foundation of China (NSFC); Grant number: 81470843.

Author information

Author notes

  1. Yunhu Bai & Yanling Yang

    Present address: Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an, 710032, China

Authors and Affiliations

  1. Department of Anatomy and K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi’an, 710032, China

    Yayun Wang

Authors
  1. Yunhu Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yayun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanling Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yanling Yang.

Ethics declarations

Conflict of interest

No.

Electronic supplementary material

Fig. S1

The purity of mitochondrial fractions in SN and PFC. *** P < 0.001, compared with the group of total protein. (JPG 121 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bai, Y., Wang, Y. & Yang, Y. Hepatic encephalopathy changes mitochondrial dynamics and autophagy in the substantia nigra. Metab Brain Dis 33, 1669–1678 (2018). https://doi.org/10.1007/s11011-018-0275-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-018-0275-6

Keywords

Search

Navigation