Post-transcriptional control of mitochondrial protein composition in changing environmental conditions

Abstract

In fluctuating environmental conditions, organisms must modulate their bioenergetic production in order to maintain cellular homeostasis for optimal fitness. Mitochondria are hubs for metabolite and energy generation. Mitochondria are also highly dynamic in their function: modulating their composition, size, density, and the network-like architecture in relation to the metabolic demands of the cell. Here, we review the recent research on the post-transcriptional regulation of mitochondrial composition focusing on mRNA localization, mRNA translation, protein import, and the role that dynamic mitochondrial structure may have on these gene expression processes. As mitochondrial structure and function has been shown to be very important for age-related processes, including cancer, metabolic disorders, and neurodegeneration, understanding how mitochondrial composition can be affected in fluctuating conditions can lead to new therapeutic directions to pursue.

Keywords: mRNA; mRNA localization; mRNA translation; mitochondria; mitochondrial morphology; protein import.

Figure 1.. Interrelationship between cellular conditions, gene expression, and mitochondrial morphology with each other on the mitochondrial activity of the cell.

The reconstructed mitochondrial morphology in fermentative, respiratory condition, and aged yeast cells are shown below. These active morphological changes are regulated by gene regulatory networks in different cellular states such as metabolic function of the cell and disease phenotypes and has a close relationship with mitochondrial activity.

Figure 2.. Metabolic state affects mitochondrial surface area and may contribute to TOM complex polymer composition.

(A) Surface area of yeast mitochondria in fermentative and respiratory condition was measured from fluorescent microscopy image processed by MitoGraph (N>112). Mean of the area for fermentative and respiratory was 48μm² and 79μm² respectively. (B) Cartoon of the typical mitochondrial morphology in fermentative (left) and respiratory (right) condition. (C) Cartoon of potential TOM complex polymer composition in fermentative (left) and respiratory (right) condition. Conditional changes may cause an alteration of protein import machinery architecture.

Figure 3.. Nuclear-encoded mRNA localization to mitochondria and potential regulatory mechanism in changing environmental condition

After the export form nuclear pore, nuclear-encoded mitochondrial mRNAs are diffusively localized to mitochondrial surface by binding to mitochondrial protein import machinery, TOM complex. The interaction between mRNA and Protein import machinery are summarized in the right box. Briefly, mRNAs bind mitochondria through a mitochondrial targeting signal in the nascent polypeptide chain. Targeting signal associates with Tom20 and Tom70 with the help of chaperone proteins Hsp70 and Djp1. Pumilio family protein (Puf3 in yeast and CLUH in mammalian cells) directly bind mRNA in a sequence-dependent manner. Association of ribosomes to OM14 and OM45 are also reported.

Figure 4.. Treatment with the translation elongation inhibitor cycloheximide (CHX) can increase the mitochondrial localization of mitochondrial protein coding mRNAs.

Cumulative distribution of mRNA enrichment (ribosome reads) to mitochondria of mitochondrial genes and all genes of (A) yeast cells measured by proximity specific ribosome profiling (68) and (B) HEK293T cells measured by APEX-seq (66) were depicted with or without addition of CHX.