Benzoni Patrizia, Da Dalt Lorenzo, Elia Noemi, Popolizio Vera, Cospito Alessandro, Giannetti Federica, Dell'Era Patrizia, Olesen Morten S, Bucchi Annalisa, Baruscotti Mirko, Norata Giuseppe Danilo, Barbuti Andrea
The Cell Physiology MiLab, Department Biosciences, Università degli Studi di Milano, Milano, Italy.
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.
Front Physiol. 2023 Nov 13;14:1250951. doi: 10.3389/fphys.2023.1250951. eCollection 2023.
Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide; however, the underlying causes of AF initiation are still poorly understood, particularly because currently available models do not allow in distinguishing the initial causes from maladaptive remodeling that induces and perpetuates AF. Lately, the genetic background has been proven to be important in the AF onset. iPSC-derived cardiomyocytes, being patient- and mutation-specific, may help solve this diatribe by showing the initial cell-autonomous changes underlying the development of the disease. Transcription factor paired-like homeodomain 2 (PITX2) has been identified as a key regulator of atrial development/differentiation, and the genomic locus has the highest association with paroxysmal AF. PITX2 influences mitochondrial activity, and alterations in either its expression or function have been widely associated with AF. In this work, we investigate the activity of mitochondria in iPSC-derived atrial cardiomyocytes (aCMs) obtained from a young patient (24 years old) with paroxysmal AF, carrying a gain-of-function mutation in (rs138163892) and from its isogenic control (CTRL) in which the heterozygous point mutation has been reverted to WT. PITX2 aCMs show a higher mitochondrial content, increased mitochondrial activity, and superoxide production under basal conditions when compared to CTRL aCMs. However, increasing mitochondrial workload by FCCP or β-adrenergic stimulation allows us to unmask mitochondrial defects in PITX2 aCMs, which are incapable of responding efficiently to the higher energy demand, determining ATP deficiency.
心房颤动（AF）是全球最常见的心律失常；然而，AF起始的潜在原因仍知之甚少，特别是因为目前可用的模型无法区分引发AF并使其持续存在的初始原因与适应性重塑。最近，遗传背景已被证明在AF发病中很重要。诱导多能干细胞（iPSC）衍生的心肌细胞具有患者特异性和突变特异性，可能有助于通过展示疾病发展背后的初始细胞自主变化来解决这一争论。转录因子配对样同源结构域2（PITX2）已被确定为心房发育/分化的关键调节因子，其基因组位点与阵发性AF的关联性最高。PITX2影响线粒体活性，其表达或功能的改变与AF广泛相关。在这项研究中，我们研究了从一名患有阵发性AF的年轻患者（24岁）获得的iPSC衍生的心房心肌细胞（aCMs）中线粒体的活性，该患者携带PITX2（rs138163892）功能获得性突变，以及来自其杂合点突变已恢复为野生型（WT）的同基因对照（CTRL）的线粒体活性。与CTRL aCMs相比，PITX2 aCMs在基础条件下显示出更高的线粒体含量、增加的线粒体活性和超氧化物产生。然而，通过羰基氰化物-4-（三氟甲氧基）苯基腙（FCCP）或β-肾上腺素能刺激增加线粒体工作量，使我们能够揭示PITX2 aCMs中的线粒体缺陷，这些细胞无法有效应对更高的能量需求，从而导致ATP缺乏。
