SFXN2 contributes mitochondrial dysfunction-induced apoptosis as a substrate of Parkin

Shishi Luo¹yechuan he²yaohui He¹danling Wang^1*

• ¹Institute for Future Sciences, Hengyang Medical School, University of South China, Changsha, China
• ²Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Mitochondria, situated at the center of intricate signaling networks, play crucial roles in maintaining health and driving disease progression. SFXN2, a recently identified member of the mitochondrial transporter family, is localized to the outer mitochondrial membrane and regulates several critical mitochondrial functions, including iron metabolism, heme biosynthesis, bioenergetics, and redox homeostasis. New evidence also suggests a connection between SFXN2 and mitochondrial dysfunction-related human diseases such as Parkinson's disease (PD). Despite growing insights into SFXN2's roles across various mitochondrial functions, its regulation under mitochondrial dysfunction and the resulting biological consequences remains unclear. In this study, we identify SFXN2 as a key regulator of mitochondrial homeostasis, demonstrating that its level is tightly regulated via Parkin-mediated ubiquitination and proteasomal degradation. Under conditions of mitochondrial damage, Parkin enhances the degradation of SFXN2, and the reduction of SFXN2 contributes to apoptotic cell death. Functional studies across multiple cell lines, including HEK293, SH-SY5Y, and N2a cells, reveal that the reduction of SFXN2 exacerbates mitochondrial damageinduced apoptosis, whereas overexpression of SFXN2 exhibits an anti-apoptotic effect. Our findings offer new insights into the regulation of SFXN2 in mitochondrial dysfunction through Parkin-mediated ubiquitin-proteasome system activity, underscoring SFXN2's potential implications in neurodegenerative diseases, particularly PD.