A role for peroxisome proliferator-activated receptor γ coactivator-1 in the control of mitochondrial dynamics during postnatal cardiac growth

OJ Martin, L Lai, MM Soundarapandian… - Circulation …, 2014 - Am Heart Assoc
OJ Martin, L Lai, MM Soundarapandian, TC Leone, A Zorzano, MP Keller, AD Attie
Circulation research, 2014Am Heart Assoc
Rationale: Increasing evidence has shown that proper control of mitochondrial dynamics
(fusion and fission) is required for high-capacity ATP production in the heart. Transcriptional
coactivators, peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) α and PGC-
1β, have been shown to regulate mitochondrial biogenesis in the heart at the time of birth.
The function of PGC-1 coactivators in the heart after birth has been incompletely understood.
Objective: Our aim was to assess the role of PGC-1 coactivators during postnatal cardiac …
Rationale
Increasing evidence has shown that proper control of mitochondrial dynamics (fusion and fission) is required for high-capacity ATP production in the heart. Transcriptional coactivators, peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) α and PGC-1β, have been shown to regulate mitochondrial biogenesis in the heart at the time of birth. The function of PGC-1 coactivators in the heart after birth has been incompletely understood.
Objective
Our aim was to assess the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts in mice.
Methods and Results
Conditional gene targeting was used in mice to explore the role of PGC-1 coactivators during postnatal cardiac development and in adult hearts. Marked mitochondrial structural derangements were observed in hearts of PGC-1α/β–deficient mice during postnatal growth, including fragmentation and elongation, associated with the development of a lethal cardiomyopathy. The expression of genes involved in mitochondrial fusion (Mfn1, Opa1) and fission (Drp1, Fis1) was altered in the hearts of PGC-1α/β–deficient mice. PGC-lα was shown to directly regulate Mfn1 gene transcription by coactivating the estrogen-related receptor α on a conserved DNA element. Surprisingly, PGC-1α/β deficiency in the adult heart did not result in evidence of abnormal mitochondrial dynamics or heart failure. However, transcriptional profiling demonstrated that PGC-1 coactivators are required for high-level expression of nuclear- and mitochondrial-encoded genes involved in mitochondrial dynamics and energy transduction in the adult heart.
Conclusions
These results reveal distinct developmental stage–specific programs involved in cardiac mitochondrial dynamics.
Am Heart Assoc