Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression

Mahmoud Abueid (1) , Donna Mcallister (1) , Laura Mcolash (1) , Megan Harwig (1) , Gang Cheng (1) , Donovan Drouillard (1) , Kathleen Boyle (1) , Micael Hardy (2) , Jacek Zielonka (1) , Bryon Johnson (1) , R Hill (1) , Balaraman Kalyanaraman (1) , Michael Dwinell (1)

1 MCW - Medical College of Wisconsin [Milwaukee]
2 ICR - Institut de Chimie Radicalaire

Metabolic heterogeneity within the tumor microenvironment promotes cancer cell growth and immune suppression. We determined the impact of mitochondria-targeted complex I inhibitors (Mito-CI) in melanoma. Mito-CI decreased mitochondria complex I oxygen consumption, Akt-FOXO signaling, blocked cell cycle progression, melanoma cell proliferation and tumor progression in an immune competent model system. Immune depletion revealed roles for T cells in the antitumor effects of Mito-CI. While Mito-CI preferentially accumulated within and halted tumor cell proliferation, it also elevated infiltration of activated effector T cells and decreased myeloid-derived suppressor cells (MDSC) as well as tumor-associated macrophages (TAM) in melanoma tumors in vivo. Anti-proliferative doses of Mito-CI inhibited differentiation, viability, and the suppressive function of bone marrow-derived MDSC and increased proliferation-independent activation of T cells. These data indicate that targeted inhibition of complex I has synchronous effects that cumulatively inhibits melanoma growth and promotes immune remodeling.

Keywords: Components of the immune system; Cell biology; Cancer

Domains: Chemical Sciences

Mahmoud Abueid, Donna Mcallister, Laura Mcolash, Megan Harwig, Gang Cheng, et al.. Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression. iScience, 2021, 24 (6), pp.102653. ⟨10.1016/j.isci.2021.102653⟩. ⟨hal-03627837⟩