Mitochondrial modulators improve lipid composition and attenuate memory deficits in experimental model of Huntington’s disease Arpit Mehrotra 1 • Abhilasha Sood 1 • Rajat Sandhir 1 Received: 30 April 2015 / Accepted: 3 September 2015 Ó Springer Science+Business Media New York 2015 Abstract 3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces neu- ropathological changes similar to those observed in Hunt- ington’s disease (HD). The objective of the present study was to investigate neuroprotective effect of mitochondrial mod- ulators; alpha-lipoic acid (ALA) and acetyl-L-carnitine (ALCAR) on 3-NP-induced alterations in mitochondrial lipid composition, mitochondrial structure and memory functions. Experimental model of HD was developed by administering 3-NP at sub-chronic doses, twice daily for 17 days. The levels of conjugated dienes, cholesterol and glycolipids were significantly increased, whereas the levels of phospholipids (phosphatidylethanolamine, phos- phatidylcholine, phosphatidylserine) including cardiolipin were significantly decreased in the mitochondria isolated from the striatum of 3-NP-treated animals. In addition, the difference in molecular composition of each phospholipid class was also evaluated using mass spectrometry. Mito- chondria lipid from 3-NP-treated animals showed increased cholesterol to phospholipid ratio, suggesting decreased mitochondrial membrane fluidity. 3-NP administration also resulted in ultra-structural changes in mitochondria, accompanied by swelling as assessed by transmission elec- tron microscopy. The 3-NP administered animals had impaired spatial memory evaluated using elevated plus maze test. However, combined supplementation with ALA ? ALCAR for 21 days normalized mitochondrial lipid composition, improved mitochondrial structure and ameliorated memory impairments in 3-NP-treated animals, suggesting an imperative role of these two modulators in combination in the management of HD. Keywords 3-Nitropropionic acid Á Huntington’s disease Á Alpha-lipoic acid Á Acetyl-L-carnitine Á Mitochondria Á Lipid composition Abbreviations ALA Alpha-lipoic acid ALCAR Acetyl-L-carnitine 3-NP 3-Nitropropionic acid HD Huntington’s disease PC Phosphatidylcholine PE Phosphatidylethanolamine PS Phosphatidylserine CL Cardiolipin Introduction HD is an autosomal-dominant inherited neurodegenerative disorder caused by an abnormally increased number of CAG trinucleotide repeats within the htt gene (also called as interesting transcript-15 or IT-15 gene), which is located on the short arm of chromosome number four [1]. Neu- ropathologically, HD is primarily characterized by neu- ronal loss in striatum and cortex. In the striatum, medium- sized spiny neurons are most affected, and degeneration of these neurons occurs in a progressive manner [2]. Neu- rodegeneration is a prolonged process in HD, as evident by signs of chronic neuroplasticity and slow involution of neurons with gradual loss of synapses, dendritic spines, dendritic branches, including axonal segments [3]. The other pathological features observed in HD include loss of mitochondria and other supporting cytoplasmic organelles & Rajat Sandhir sandhir@pu.ac.in 1 Department of Biochemistry, Panjab University, Chandigarh 160014, India 123 Mol Cell Biochem DOI 10.1007/s11010-015-2561-5