Mitochondrial signaling: forwards, backwards, and in between

Abstract

Mitochondria are semiautonomous organelles that are a defining characteristic of almost all eukaryotic cells. They are vital for energy production, but increasing evidence shows that they play important roles in a wide range of cellular signaling and homeostasis. Our understanding of nuclear control of mitochondrial function has expanded over the past half century with the discovery of multiple transcription factors and cofactors governing mitochondrial biogenesis. More recently, nuclear changes in response to mitochondrial messaging have led to characterization of retrograde mitochondrial signaling, in which mitochondria have the ability to alter nuclear gene expression. Mitochondria are also integral to other components of stress response or quality control including ROS signaling, unfolded protein response, mitochondrial autophagy, and biogenesis. These avenues of mitochondrial signaling are discussed in this review.

Figures

Figure 1

Diagrammatic summary of the nuclear control of mitochondrial functions by NRF-1 and NRF-2 (GABP). NRFs contribute both directly and indirectly to the expression of many genes required for the maintenance and function of the mitochondrial respiratory apparatus. NRFs act on genes encoding cytochrome c, the majority of nuclear subunits of respiratory complexes I–V, and the rate-limiting heme biosynthetic enzyme 5-aminolevulinate synthase. In addition, NRFs promote the expression of key components of the mitochondrial transcription and translation machinery that are necessary for the production of respiratory subunits encoded by mtDNA. These include Tfam, TFB1M, and TFB2M as well as a number of mitochondrial ribosomal proteins and tRNA synthetases. Recent findings suggest that NRFs are also involved in the expression of key components of the protein import and assembly machinery. Adapted with permission from [2].

Figure 2

Positive and negative regulators of the retrograde pathway. The retrograde pathway is constitutively inhibited by Mks1p as well as TOR1/2p/Lst8p which hyperphosphorylates (P) the Rtg1/3p heterodimer. Bmh1/2p stabilizes the phosphorylated Mks1p contributing to its activity and preventing its degradation. Mitochondrial stress activates Rtg2p which dephosphorylates Mks1p. Mks1p then dissociates from Bmh1/2p and is degraded by Grr1p. Rtg2p also inhibits the inhibitory factor Lst8p. Additionally, Lst8p is part of the TOR1/2p complex and is also controlled by canonical regulators of TOR. The disinhibition of the Rtg1/3p heterodimer allows dephosphorylation and translocation to the nucleus where it activates the RTG genes. The prototypical RTG gene CIT2 encodes peroxisomal citrate synthase (CIT2) which converts Acetyl-CoA and oxaloacetic acid (OAA) to citrate. This contributes nitrogen to the TCA cycle in order to maintain an adequate supply of α-ketoglutarate. Ultimately, this leads to production of glutamate which is the ultimate source of biosynthetic reactions in yeast. The plasma membrane amino acid sensor SPS inhibits Rtg2p in a negative feedback mechanism in the presence of excess glutamate.

Figure 3

Hypothetical model of the C. elegans UPRmt pathway. Protein conformational stress in the mitochondrial matrix triggers CLPP-1 proteolysis of an unknown substrate, producing a stress signal (blue line). The stress signal is conveyed to the cytoplasm and induces nuclear translocation and complex formation of UBL-5 and DVE-1, as well as binding of DVE-1 to the promoter of the chaperone target gene, HSP-60. This stress-signaling pathway results in the induction of mitochondrial chaperone genes, HSP-60 and HSP-6. ubl-5 expression is also upregulated, which in turn amplifies the UPRmt signal (green-dotted line). HSP-60 and HSP-6 are imported into the mitochondria, where they help to restore protein homeostasis by refolding rogue proteins. Adapted with permission from [51].