Protein quality control is essential for cellular homeostasis. In this study, we examined the effect of improperly folded proteins that do not form amyloid fibrils on mitochondria, which play important roles in ATP production and cell death. First, we prepared domain 3 of the dengue envelope protein in wild type and four mutants with widely different biophysical properties in misfolded/aggregated or destabilized states. The effects of the different proteins were detected using fluorescence microscopy and Western blotting, which revealed that three of the five proteins disrupted both inner and outer membrane integrity, while the other two proteins, including the wild type, did not. Next, we examined the common characteristics of the proteins that displayed toxicity against mitochondria by measuring oligomer size, molten globule-like properties, and thermal stability. The common feature of all three toxic proteins was thermal instability. Therefore, our data strongly suggest that thermally unstable proteins generated in the cytosol can cause cellular damage by coming into direct contact with mitochondria. More importantly, we revealed that this damage is not amyloid-specific.

Mitochondrial succinate dehydrogenase subunits are differentially expressed in multiple tumor types, suggesting their role as a cancer type-dependent metabolic target. However, information on the expression of SDH subunits in breast cancer (BC), particularly in South Asian populations, remains scarce. So, we analyze the expression profile of all four SDH subunits in breast cancer patients from Bangladesh. qRT-PCR was carried out to analyze the mRNA expression of four SDH subunits in Luminal A, Luminal B, Her2+, and triple-negative breast cancer subtypes and the results were compared with The Cancer Genome Atlas (TCGA) database. All four succinate dehydrogenase subunits were significantly upregulated in tumor tissues when compared to controls and showed an alignment with the TCGA except SDHD, which was significantly downregulated in TCGA. Subtype-specific analysis demonstrated differential expression patterns. SDHD upregulation has also been connected to worse outcomes for patients which indicates its role in cancer progression. Furthermore, we found a significant upregulation of METTL3 in our patient cohort. Taken together, the elevated SDHD and METTL3 expression suggests a potential epigenetic mechanism-driven SDHD activation, highlighting its previously unreported role in breast cancer biology and revealing a distinct pattern of SDH dysregulation in the Bangladeshi breast cancer population.