Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense

Mastura Akter; Haiying Ma; Mahadi Hasan; Anwarul Karim; Xiaowei Zhu; Liang Zhang; Ying Li

doi:10.3389/fnmol.2023.1117146

Exogenous L-lactate administration in rat hippocampus increases expression of key regulators of mitochondrial biogenesis and antioxidant defense

Front Mol Neurosci. 2023 Mar 16:16:1117146. doi: 10.3389/fnmol.2023.1117146. eCollection 2023.

Authors

Mastura Akter^{1

2}, Haiying Ma², Mahadi Hasan^{1

2}, Anwarul Karim³, Xiaowei Zhu¹, Liang Zhang^{2

4}, Ying Li^{1

2

5

6}

Affiliations

¹ Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
² Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
³ School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Kowloon, Hong Kong SAR, China.
⁴ Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong, Futian Research Institute, Shenzhen, Guangdong, China.
⁵ Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong, Hong Kong SAR, China.
⁶ Centre for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Kowloon, Hong Kong SAR, China.

Abstract

L-lactate plays a critical role in learning and memory. Studies in rats showed that administration of exogenous L-lactate into the anterior cingulate cortex and hippocampus (HPC) improved decision-making and enhanced long-term memory formation, respectively. Although the molecular mechanisms by which L-lactate confers its beneficial effect are an active area of investigations, one recent study found that L-lactate supplementation results in a mild reactive oxygen species burst and induction of pro-survival pathways. To further investigate the molecular changes induced by L-lactate, we injected rats with either L-lactate or artificial CSF bilaterally into the dorsal HPC and collected the HPC after 60 minutes for mass spectrometry. We identified increased levels of several proteins that include SIRT3, KIF5B, OXR1, PYGM, and ATG7 in the HPC of the L-lactate treated rats. SIRT3 (Sirtuin 3) is a key regulator of mitochondrial functions and homeostasis and protects cells against oxidative stress. Further experiments identified increased expression of the key regulator of mitochondrial biogenesis (PGC-1α) and mitochondrial proteins (ATPB, Cyt-c) as well as increased mitochondrial DNA (mtDNA) copy number in the HPC of L-lactate treated rats. OXR1 (Oxidation resistance protein 1) is known to maintain mitochondrial stability. It mitigates the deleterious effects of oxidative damage in neurons by inducing a resistance response against oxidative stress. Together, our study suggests that L-lactate can induce expression of key regulators of mitochondrial biogenesis and antioxidant defense. These findings create new research avenues to explore their contribution to the L-lactate's beneficial effect in cognitive functions as these cellular responses might enable neurons to generate more ATP to meet energy demand of neuronal activity and synaptic plasticity as well as attenuate the associated oxidative stress.

Keywords: PGC-1 alpha; SIRT3; hippocampus; lactate; mitochondrial biogenesis; oxidative stress; proteomics.