Publication Highlight: Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice

The Ndufs4 knockout mouse (Ndufs4−/−) was utilized within this research. NDUFS4 encodes for a critical component of the Mitochondrial Complex I, which is vital to proper mitochondrial functioning and metabolism​⁸​. Ndufs4−/− is a leading mouse model to study the Leigh syndrome pathophysiology within multiple tissue systems​​^9,10.  

Using the Rodent Surgical Monitoring System, the researchers acquired ECG recordings from conscious Ndufs4−/− mice for 40 – 60 minutes. The researchers then counted arrhythmic events and showed that Ndufs4−/− mice develop cardiac bradyarrhythmia, including frequent sinus node dysfunction and episodic atrioventricular (AV) block, as highlighted by the abnormal ECGs tracings shown within Figure 1.  

Treatment with Mitotempo offers targeted mitochondrial protection by reducing reactive oxygen species. The researchers used within this work to improve mitochondrial function within the heart.  Treatment with Mitotempo nearly abolished arrhythmic events by restoring normal sinus rhythm within the Ndufs4−/− mice, as shown in Figure 2 via a quantitative ECG analysis (Ndufs4−/− frequency of 62, Ndufs4−/− frequency of 62; Ndufs4−/− with treatment of Mitotempo frequency of 2.7). Survival analysis also showed that treatment with Mitotempo significantly increased survival of the Ndufs4−/− mice by 20%.  

The researchers demonstrate that mitochondrial oxidative stress is a direct mechanistic driver of bradyarrhythmia in a mouse model of Leigh Syndrome caused by Ndufs4 deficiency. Importantly, mitochondrial-targeted therapies, like Mitotempo, reduced reactive oxygen species, restored normal sinus rhythm, and significantly extended the lifespan of Ndufs4−/− mice. This work highlights mitochondrial antioxidants as promising, potentially translatable therapies for treating cardiac complications seen in Leigh Syndrome patients.