Bardoxolone methyl induces mitochondrial dysfunction, activation of the cytosolic stress response, and increased chaperone capacity in SH-SY5Y cells. Focus on mitochondrial protease LONP1.

Our work aimed to study the impact of bardoxolone methyl, 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me), on mitochondrial function and morphology in SH-SY5Y cells, molecular responses, with a focus on the expression of proteins of mitochondriaspecific unfolded protein response (mtUPR), the endoplasmic reticulum-specific UPR (UPRER), and the cytosolic stress response. Treatment of SH-SY5Y cells with CDDO-Me is associated with decreased relative cell survival associated with gasdermin E cleavage, compatible with pyroptotic cell death features. Treatment of SH-SY5Y cells with CDDO-Me results in decreased ROUTINE respiration, maximal respiration, succinate-driven maximal respiration, ATP-coupled respiration, and spare respiratory capacity. We have not observed significant changes in the expression of proteins that play important roles in both mtUPR (LONP1) and UPRER (HRD1 and SEL1L), whereas expression of cytosolic chaperone HSP70 was significantly increased in response to CDDO-Me. In addition, we have observed increased expression of mitochondrial chaperones HSP60 and GRP75 as well as ER chaperone GRP78. Finally, we have observed the formation of donut-like mitochondria induced by CDDO-Me. Our results, together with previously published data, indicate that mitochondrial dysfunction, activation of cytosolic stress response, and an increase in chaperone capacity elicited by CDDO-Me could be attributed to CDDO-Me's ability to inhibit LONP1 protease.