Peroxisome proliferator–activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis

TLDR

Cardiac mitochondrial function is altered in many cardiovascular diseases, and the transcriptional coactivator PGC‑1 has emerged as a key regulator of mitochondrial activity in thermogenic tissues. This study aimed to determine whether PGC‑1 drives mitochondrial biogenesis and energy production in the heart. PGC‑1 expression rises after birth and during fasting, and its forced cardiac expression expands mitochondrial genes, number, and respiration but, when overexpressed in mice, leads to uncontrolled mitochondrial proliferation, sarcomere loss, and dilated cardiomyopathy, underscoring PGC‑1 as a critical regulator of cardiac mitochondrial number and function in response to energy demands.

Abstract

Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator–activated receptor γ coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.