Transcriptomic and Functional Analyses of Mitochondrial Dysfunction in Pressure Overload-Induced Right Ventricular...

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Congenital Heart Disease Research

Background:

• Complex congenital heart disease, like tetralogy of Fallot, causes right ventricle (RV) pressure overload.
• This overload leads to RV hypertrophy and, ultimately, RV failure through poorly understood mechanisms.
• Mitochondrial bioenergetics' role in this transition is investigated.

Purpose of the Study:

• To evaluate the role of mitochondrial bioenergetics in the development of RV failure.
• To understand the molecular mechanisms underlying the transition from RV hypertrophy to RV failure.

Main Methods:

• A murine model of RV pressure overload was created using pulmonary artery banding.
• RNA-sequencing, oxidative stress markers, mitochondrial respiration, dynamics, and structure were assessed.
• Gene expression, enzyme activity, and protein levels were analyzed in RV tissues.

Main Results:

• RV failure showed decreased expression of electron transport chain and antioxidant genes (ALDH2, SOD2).
• Oxidative stress markers (HMOX, HNE) increased, and electron transport chain complex activity significantly declined.
• Mitochondrial fission proteins trended to increase, while fusion proteins (OPA1) decreased, indicating altered mitochondrial dynamics.

Conclusions:

• Pressure overload-induced RV failure is marked by impaired mitochondrial electron transport chain function and increased oxidative stress.
• These mitochondrial changes are linked to reduced cellular energy generation.
• Understanding these bioenergetic alterations could lead to novel therapeutic strategies for RV failure.