攜帶母系遺傳突變粒線體的小鼠產生葡萄糖耐受不良與胰島素敏感性降低

Abstract

第二型糖尿病是一種常見的慢性代謝性疾病，其主要特徵之一是胰島素抵抗。然而，至今對胰島素抵抗的形成機制仍未有明確的定論。近年來的研究指出，粒線體功能異常與胰島素訊號傳遞障礙之間存在密切關聯，但兩者之間的因果關係及其調控機制仍待進一步釐清。 本研究聚焦於 SUPV3L1(SUV3)的功能與代謝異常之間的關係。SUV3是粒線體RNA降解體中的關鍵成員，主要負責粒線體內RNA的穩定性與代謝調節。在小鼠模型中，缺失SUV3會造成粒線體DNA的突變累積，進而引發粒線體功能受損，而這些異常可經由母系遺傳傳遞給下一代。 透過SUV3缺失小鼠模型，我們發現下一代在代謝功能上出現異常，包括葡萄糖耐受不良、胰島素敏感性下降，並且在骨骼肌中蛋白激酶(Akt)的磷酸化程度也顯著降低，顯示胰島素訊號傳遞路徑遭受干擾。同時，mtDNAmaternal mutation小鼠的血液中游離脂肪酸濃度偏高，並伴隨運動耐力下降。進一步利用間接熱量測量法分析其能量來源，發現mtDNAmaternal mutation小鼠在非運動狀態下的代謝偏好使用碳水化合物作為能量來源，且mtDNAmaternal mutation小鼠在脂肪酸代謝及電子傳遞鏈的活性也顯著降低，顯示粒線體功能受損對脂肪酸代謝產生影響。 綜上所述，我們認為 SUV3 的缺失不僅會損害粒線體功能，還會透過干擾肌肉細胞中的胰島素訊號傳遞而導致胰島素抵抗，進一步干擾代謝平衡。本研究提供了粒線體與胰島素抵抗之間可能機制的證據，也為未來探討粒線體相關疾病，特別是糖尿病的發病途徑提供了一個潛在的研究方向。

Type 2 diabetes is a prevalent chronic disease involving insulin resistance, with the cause of this resistance still not fully understood. Previous research has found a strong connection between insulin resistance and mitochondrial dysfunction and, but the casual relationship and specific mechanisms remain unclear. Recent studies highlight a strong association between mitochondrial dysfunction and impaired insulin signaling. However, the relationship and detailed molecular pathways are still under investigation. In this study, we chose to investigate the regulation of SUV3, which is a component of the mitochondrial RNA degradosome responsible for the metabolism and regulation of mitochondrial RNA. Deletion of SUV3 in mice can lead to mitochondrial DNA mutations and a decrease in mitochondrial function, and these phenotypes can be maternally inherited to the next generation. Our research found that mice inheriting mitochondrial DNA mutations could develop glucose intolerance and insulin resistance, along with a significant decrease in skeletal muscle Akt phosphorylation. We further revealed that mice inheriting mitochondrial DNA mutations maternally also have higher free fatty acid in the blood and decreased exercise tolerance. Indirect calorimetry measurements showed a reduced proportion of fatty acid burning in these mice. In addition, the activity of Fatty acid oxidation and oxidative phosphorylation are reduced mice with mitochondrial DNA mutation mice, suggesting that mitochondrial dysfunction affect β-oxidation. We found that SUV3 deletion leads to a decrease in Akt phosphorylation in skeletal muscle, affecting the insulin signaling pathway and thus causing insulin resistance. These new research findings can be beneficial to clinical studies for diabetes patients.