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Mitochondrial dysfunctions contribute to energy deficits in rodent model of hepatic encephalopathy

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Abstract

Perturbations in the cerebral energy metabolism are anticipated to be an important factor by which ammonia may exert its toxic effects on the central nervous system. The present study was designed to investigate the role of impaired mitochondrial functions and cerebral energy metabolism in the development hepatic encephalopathy (HE) induced by of bile duct ligation (BDL). After four weeks of BDL, a significant increase in hepatic hydroxyproline and collagen content was observed which confirmed biliary fibrosis. Brain regions viz. cortex, hippocampus, striatum and cerebellum of BDL rats had impaired activity of mitochondrial respiratory chain enzymes. This was accompanied by increase in mitochondrial reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl levels in the brain. Mitochondrial redox ratio was significantly reduced in the brain of BDL rats. In addition, mitochondria from brain of BDL rats were depolarized and swollen compared to the sham controls. Ultrastructure analysis of mitochondria from cortex and hippocampus of BDL animals revealed aberrant cristae, ruptured membranes and non-dense matrix. Further, a significant decrease was observed in creatine kinase activity, glucose uptake and CO2 production in the brain regions of BDL rats. ATP/ADP ratio, a critical parameter of cellular energy status, was also significantly reduced in brain regions of rats with HE. Overall, the findings clearly demonstrate that BDL induced HE involves mitochondrial respiratory chain dysfunctions, mitochondrial depolarization and swelling that accentuates oxidative stress which in turn leads to compromise in cerebral energy metabolism thereby contributing to the pathophysiology of chronic HE.

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Abbreviations

AASLD:

American association for the study of the liver diseases

BDL:

Bile duct ligation

BSA:

Bovine serum albumin

EASL:

European association for the study of the liver

EDTA:

Ethylene diamine tetra acetic acid

ETC:

Electron transport chain

HE:

Hepatic encephalopathy

GSH:

Glutathione

GSSG:

Oxidized glutathione

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

ISHEN:

International society for hepatic encephalopathy and nitrogen metabolism

MDA:

Malondialdehyde

PBS:

Phosphate buffer saline

RLU:

Relative light units

ROS:

Reactive oxygen species

SC:

Sham control

SDS:

Sodium dodecyl sulphate

SEM:

Standard error mean

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Acknowledgements

The financial assistance provided by Department of Science and Technology (DST), New Delhi, under the Promotion of University Research and Scientific Excellence (PURSE) grant and the University Grants Commission-Special Assistance Programme (UGC-SAP) Departmental Research Support-II (DRS-II) is acknowledged. Aditya Sunkaria has recieved financial assistance by Department of Science and Technology, New Delhi, under the Startup Research Grant for Young Scientists Scheme.

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  1. Department of Biochemistry, Panjab University, Basic Medical Science Block-II, Sector-25, Chandigarh, 160014, India

    Saurabh Dhanda, Aditya Sunkaria, Avishek Halder & Rajat Sandhir

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  1. Saurabh Dhanda
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Correspondence to Rajat Sandhir.

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Dhanda, S., Sunkaria, A., Halder, A. et al. Mitochondrial dysfunctions contribute to energy deficits in rodent model of hepatic encephalopathy. Metab Brain Dis 33, 209–223 (2018). https://doi.org/10.1007/s11011-017-0136-8

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