Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics

Abstract

Mitochondria play a central role not only in energy production but also in the integration of metabolic pathways as well as signals for apoptosis and autophagy. It is becoming increasingly apparent that mitochondria in mammalian cells play critical roles in the initiation and propagation of various signaling cascades. In particular, mitochondrial metabolic and respiratory states and status on mitochondrial genetic instability are communicated to the nucleus as an adaptive response through retrograde signaling. Each mammalian cell contains multiple copies of the mitochondrial genome (mtDNA). A reduction in mtDNA copy number has been reported in various human pathological conditions such as diabetes, obesity, neurodegenerative disorders, aging and cancer. Reduction in mtDNA copy number disrupts mitochondrial membrane potential (Δψm) resulting in dysfunctional mitochondria. Dysfunctional mitochondria trigger retrograde signaling and communicate their changing metabolic and functional state to the nucleus as an adaptive response resulting in an altered nuclear gene expression profile and altered cell physiology and morphology. In this review, we provide an overview of the various modes of mitochondrial retrograde signaling focusing particularly on the Ca(2+)/Calcineurin mediated retrograde signaling. We discuss the contribution of the key factors of the pathway such as Calcineurin, IGF1 receptor, Akt kinase and HnRNPA2 in the propagation of signaling and their role in modulating genetic and epigenetic changes favoring cellular reprogramming towards tumorigenesis.

Keywords: Calcineurin; Cancer; Epigenetics; HnRNPA2; Mitochondrial DNA; Mitochondrial retrograde signaling.

Figure 1. Outline of the two major mitochondrial signaling pathways

(A) Anterograde signaling is transmitted by activated nuclear transcription factors and cytoplasmic proteins essential for mitochondrial biogenesis. (B) Retrograde signaling originates in dysfunctional mitochondria and communicated to the nucleus resulting in altered expression of nuclear genes.

Figure 2. Schematic outline of the reduced mtDNA copy number mediated mitochondrial retrograde signaling in C2C12 myocytes

Reduction of mtDNA content below 70% disrupts ΔΨm which results in elevated cytosolic Ca²⁺ and activation of Calcineurin. This initiates a signaling pathway involving a number of kinases and transcription factors along with a mitochondrial stress activated transcriptional coactivator, hnRNPA2. The resultant of this signaling is an upregulation of nuclear genes leading to cellular reprogramming towards tumorigenesis.

Figure 3. Functional Domains of hnRNPA2

A cartoon of the different functional domains of human hnRNPA2 identified till date. The residues 1–180 are the two RNA recognition motifs (RRM) which are involved RNA binding and transcriptional activation; residues 181–341 is the glycine rich domain involved in protein-protein interaction. The Akt phosphorylation sites Thr 98 and Ser 213 are indicated in green.

Figure 4. Schematic outline of the key aspects of the Calcineurin mediated mitochondrial retrograde signaling

The essential components of the Cn-mediated retrograde signaling pathway. In response to this stress signal, NFκB (cRel-p50) and the other signature transcription factors (as indicated) alongwith hnRNPA2 and Akt kinase are activated and translocated to the nucleus. Nuclear Akt phosphorylates hnRNPA2 which associates with the signature transcription factors by protein-protein interaction and stabilizes the enhanceosome complex. The transcriptional coactivator function of hnRNPA2 is essential for activation of the stress responsive nuclear genes Cathepsin L, RyR1, Glut4 and Akt1.