A Mathematical Exploration of SDH-b Loss in Chromaffin Cells.

IF 2 4区 数学 Q2 BIOLOGY
Elías Vera-Sigüenza, Himani Rana, Ramin Nashebi, Ielyaas Cloete, Katarína Kl'uvčková, Fabian Spill, Daniel A Tennant
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引用次数: 0

Abstract

The succinate dehydrogenase (SDH) is a four-subunit enzyme complex (SDH-a, SDH-b, SDH-c, and SDH-d) central to cell carbon metabolism. The SDH bridges the tricarboxylic acid cycle to the electron transport chain. A pathological loss of the SDH-b subunit leads to a cell-wide signalling cascade that shifts the cell's metabolism into a pseudo-hypoxic state akin to the so-called Warburg effect (or aerobic glycolysis). This trait is a hallmark of phaeochromocytomas, a rare tumour arising from chromaffin cells; a type of cell that lies in the medulla of the adrenal gland. In this study, we leverage the insights from a mathematical model constructed to underpin the metabolic implications of SDH-b dysfunction in phaeochromocytomas. We specifically investigate why chromaffin cells seemingly have the ability to maintain electron transport chain's Complex I function when confronted with the loss of the SDH-b subunit while other cells do not. Our simulations indicate that retention of Complex I is associated with cofactor oxidation, which enables cells to manage mitochondrial swelling and limit the reversal of the adenosine triphosphate synthase, supporting cell fitness, without undergoing lysis. These results support previous hypotheses that point to mitochondrial proton leaks as a critical factor of future research. Moreover, the model asserts that control of the proton gradient across the mitochondrial inner membrane is rate-limiting upon fitness management of SDH-b deficient cells.

染色质细胞中SDH-b损失的数学探讨。
琥珀酸脱氢酶(SDH)是一种四亚基酶复合物(SDH-a、SDH-b、SDH-c和SDH-d),对细胞碳代谢至关重要。SDH将三羧酸循环连接到电子传递链上。SDH-b亚基的病理性缺失导致全细胞范围的信号级联,将细胞代谢转变为类似于所谓的Warburg效应(或有氧糖酵解)的伪缺氧状态。这一特征是嗜铬细胞瘤的标志,嗜铬细胞瘤是一种罕见的由嗜铬细胞引起的肿瘤;肾上腺髓质一种位于肾上腺髓质的细胞在这项研究中,我们利用构建的数学模型的见解来支持嗜铬细胞瘤中SDH-b功能障碍的代谢意义。我们专门研究了为什么当面临SDH-b亚基缺失时,染色质细胞似乎有能力维持电子传递链的复合物I功能,而其他细胞却没有。我们的模拟表明,复合物I的保留与辅因子氧化有关,辅因子氧化使细胞能够控制线粒体肿胀并限制三磷酸腺苷合成酶的逆转,从而支持细胞适应性,而无需进行溶解。这些结果支持了先前的假设,即线粒体质子泄漏是未来研究的关键因素。此外,该模型断言,对线粒体内膜上质子梯度的控制对SDH-b缺陷细胞的适应度管理是限速的。
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来源期刊
CiteScore
3.90
自引率
8.60%
发文量
123
审稿时长
7.5 months
期刊介绍: The Bulletin of Mathematical Biology, the official journal of the Society for Mathematical Biology, disseminates original research findings and other information relevant to the interface of biology and the mathematical sciences. Contributions should have relevance to both fields. In order to accommodate the broad scope of new developments, the journal accepts a variety of contributions, including: Original research articles focused on new biological insights gained with the help of tools from the mathematical sciences or new mathematical tools and methods with demonstrated applicability to biological investigations Research in mathematical biology education Reviews Commentaries Perspectives, and contributions that discuss issues important to the profession All contributions are peer-reviewed.
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