A Systems Approach for Decoding Mitochondrial Retrograde Signaling Pathways

Abstract

Mitochondrial dysfunctions activate retrograde signaling from mitochondria to the nucleus. To identify transcription factors and their associated pathways that underlie mitochondrial retrograde signaling, we performed gene expression profiling of the cells engineered to have varying amounts of mitochondrial DNA with an A3243G mutation (mt3243) in the leucine transfer RNA (tRNA(Leu)), which reduces the abundance of proteins involved in oxidative phosphorylation that are encoded by the mitochondrial genome. The cells with the mutation exhibited reduced mitochondrial function, including compromised oxidative phosphorylation, which would activate diverse mitochondrial retrograde signaling pathways. By analyzing the gene expression profiles in cells with the mutant tRNA(Leu) and the transcription factors that recognize the differentially regulated genes, we identified 72 transcription factors that were potentially involved in mitochondrial retrograde signaling. We experimentally validated that the mt3243 mutation induced a retrograde signaling pathway involving RXRA (retinoid X receptor α), reactive oxygen species, kinase JNK (c-JUN N-terminal kinase), and transcriptional coactivator PGC1α (peroxisome proliferator-activated receptor γ, coactivator 1 α). This RXR pathway contributed to the decrease in mRNA abundances of oxidative phosphorylation enzymes encoded in the nuclear genome, thereby aggravating the dysfunction in oxidative phosphorylation caused by the reduced abundance of mitochondria-encoded enzymes of oxidative phosphorylation. Thus, matching transcription factors to differentially regulated gene expression profiles was an effective approach to understand mitochondrial retrograde signaling pathways and their roles in mitochondrial dysfunction.

A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle

“…45). In mammalian cells with an A3242G mutation of mitochondrial DNA, mitochondrial dysfuction altered expressions of several transcription factors including RXRA, which led to the decrease in PGC-1a recruitment and the repression of oxidative phosphorylation genes 46 . The involvement of PGC-1b in the retrograde signalling has not been reported, however, Pgc-1b may also have a role in the pathological condition of Cox7rpKO mice similar to Pgc-1a.…”

Elevated oxidative damage is correlated with reduced fitness in interpopulation hybrids of a marine copepod

“…Because previous work has shown that hybrid mitochondria in T. californicus have reduced ATP synthetic capacity [21], energy for preventive antioxidant activity and energy to repair damage is possibly reduced in hybrids. In addition to causing damage to cellular components, increased ROS levels activate numerous retrograde signalling pathways from mitochondria to the nucleus, which alter expression of many genes in both genomes and can affect important metabolic processes [48,49]. Moreover, dysfunctional ROS metabolism may undergo a positive feedback loop: increased oxidative damage can increase mitochondrial dysfunction, promoting further ROS accumulation [25,29].…”

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

“…In Drosophila, disruption of respiratory complex 1 signals to components of the G1 to S cell cycle machinery trough JNK and FoxO (Owusu-Ansah et al 2008). In mammalian cells, a similar retrograde signaling has been uncovered through a systematic analysis of different mitochondrial dysfunction mutations; this pathway increases OXPHOS genes and involves ROS signaling through JNK and the RXRa/ PGC1a pathway (Chae et al 2013). …”