The SARS-CoV-2 spike glycoprotein interacts with MAO-B and impairs mitochondrial energetics

Chantal A Pileggi; Gaganvir Parmar; Hussein Elkhatib; Corina M Stewart; Irina Alecu; Marceline Côté; Steffany A L Bennett; Jagdeep K Sandhu; Miroslava Cuperlovic-Culf; Mary-Ellen Harper

doi:10.1016/j.crneur.2023.100112

The SARS-CoV-2 spike glycoprotein interacts with MAO-B and impairs mitochondrial energetics

Curr Res Neurobiol. 2023 Oct 6:5:100112. doi: 10.1016/j.crneur.2023.100112. eCollection 2023.

Authors

Chantal A Pileggi^{1

2

3}, Gaganvir Parmar^{1

2}, Hussein Elkhatib^{1

2}, Corina M Stewart^{1

2

4}, Irina Alecu^{1

2

5}, Marceline Côté^{1

2

6}, Steffany A L Bennett^{1

2

5}, Jagdeep K Sandhu^{1

2

6

7}, Miroslava Cuperlovic-Culf^{1

2

3}, Mary-Ellen Harper^{1

2

6}

Affiliations

¹ Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
² Ottawa Institute of Systems Biology, University of Ottawa, ON, K1H 8M5, Canada.
³ National Research Council of Canada, Digital Technologies Research Centre, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada.
⁴ Current Address: Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁵ Neural Regeneration Laboratory, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
⁶ Centre for Infection, Immunity and Inflammation, University of Ottawa, ON, K1H 8M5, Canada.
⁷ Human Health Therapeutics Research Centre, National Research Council Canada, 1200 Montreal Road, Ottawa, ON, K1A 0R6, Canada.

Abstract

SARS-CoV-2 infection is associated with both acute and post-acute neurological symptoms. Emerging evidence suggests that SARS-CoV-2 can alter mitochondrial metabolism, suggesting that changes in brain metabolism may contribute to the development of acute and post-acute neurological complications. Monoamine oxidase B (MAO-B) is a flavoenzyme located on the outer mitochondrial membrane that catalyzes the oxidative deamination of monoamine neurotransmitters. Computational analyses have revealed high similarity between the SARS-CoV-2 spike glycoprotein receptor binding domain on the ACE2 receptor and MAO-B, leading to the hypothesis that SARS-CoV-2 spike glycoprotein may alter neurotransmitter metabolism by interacting with MAO-B. Our results empirically establish that the SARS-CoV-2 spike glycoprotein interacts with MAO-B, leading to increased MAO-B activity in SH-SY5Y neuron-like cells. Common to neurodegenerative disease pathophysiological mechanisms, we also demonstrate that the spike glycoprotein impairs mitochondrial bioenergetics, induces oxidative stress, and perturbs the degradation of depolarized aberrant mitochondria through mitophagy. Our findings also demonstrate that SH-SY5Y neuron-like cells expressing the SARS-CoV-2 spike protein were more susceptible to MPTP-induced necrosis, likely necroptosis. Together, these results reveal novel mechanisms that may contribute to SARS-CoV-2-induced neurodegeneration.

Keywords: Mitochondria; Monoamine oxidase B; Parkinson's disease; SARS-CoV-2.