線粒體是重要的細胞器，負責調節細胞能量代謝、生物合成和訊號傳導，其功能高度依賴於線粒體DNA（mtDNA）的完整性。在酵母菌（Saccharomyces cerevisiae）中，失去mtDNA會導致呼吸缺陷的小型表型，提供了一個強健的模型來研究線粒體基因組的穩定性和品質控制。雖然線粒體的品質控制主要由線粒體內部的機制調節，但越來越多的證據表明，線粒體外的蛋白質穩定性途徑也可能影響線粒體的穩態。 內質網相關降解（ERAD）途徑是一個核心的蛋白質品質控制系統，負責識別和降解內質網中的錯誤摺疊蛋白。雖然ERAD在維持內質網蛋白質穩態方面已有較完整的研究，但其對線粒體基因組穩定性的影響仍不清楚。本研究旨在探討破壞ERAD組分是否會影響酵母（Saccharomyces cerevisiae）的線粒體品質控制和線粒體DNA穩定性。 線粒體基因組的不穩定性是使用小型頻率測試在溴化乙錠誘導的壓力條件下評估的。生成了一系列針對 ERAD-L、ERAD-M 和 ERAD-C 組件的基因刪除株。總體而言，ERAD 並不作為線粒體基因組穩定性的統一調控因子。它對線粒體品質控制的貢獻具有途徑特異性，且大多是間接的，如通過泛素穩態、蛋白質穩定性平衡和應激反應信號介導。這些研究結果突顯了線粒體基因組完整性主要由內在線粒體機制維持，並能緩衝與 ER 相關降解途徑的干擾。;Mitochondria are essential organelles that regulate cellular energy metabolism， biosynthesis， and signaling， and their function critically depend on the integrity of mitochondrial DNA (mtDNA). In Saccharomyces cerevisiae， loss of mtDNA results in respiratory-deficient petite phenotypes， providing a robust model to investigate mitochondrial genome stability and quality control. While mitochondrial quality control is largely governed by intra-mitochondrial mechanisms， increasing evidence suggests that extramitochondrial proteostasis pathways may also influence mitochondrial homeostasis. The endoplasmic reticulum-associated degradation (ERAD) pathway is a central protein quality control system responsible for the recognition and degradation of misfolded protein in endoplasmic reticulum. Although ERAD is well characterized in maintaining ER proteostasis， its contribution in mitochondrial DNA quality control (mtDNA QC) is remained poorly defined. This study aims to investigate whether disruption of ERAD components affects mitochondrial DNA quality control (mtDNA QC) in Saccharomyces cerevisiae. Mitochondrial DNA quality control (mtDNA QC) was assessed using petite frequency assays under ethidium bromide-induced stress conditions. A series of gene deletion strains targeting ERAD-L， ERAD-M and ERAD-C components were generated. Overall， ERAD does not acts as a uniform regulator of mitochondrial genome stability. Its contribution to mitochondrial DNA quality control (mtDNA QC) is pathway substrate-specific and largely indirectly， like mediated through ubiquitin homeostasis， proteostasis balance， and stress-response signaling. These findings highlight that mitochondrial genome integrity is primarily maintained by intrinsic mitochondrial mechanisms buffered against disruption of ER-associated degradation pathways.
