Keep in touch: a perspective on the mitochondrial social network and its implication in health and disease

Abstract

Mitochondria have been the focus of extensive research for decades since their dysfunction is linked to more than 150 distinct human disorders. Despite considerable efforts, researchers have only been able to skim the surface of the mitochondrial social complexity and the impact of inter-organelle and inter-organ communication alterations on human health. While some progress has been made in deciphering connections among mitochondria and other cytoplasmic organelles through direct (i.e., contact sites) or indirect (i.e., inter-organelle trafficking) crosstalk, most of these efforts have been restricted to a limited number of proteins involved in specific physiological pathways or disease states. This research bottleneck is further narrowed by our incomplete understanding of the cellular alteration timeline in a specific pathology, which prevents the distinction between a primary organelle dysfunction and the defects occurring due to the disruption of the organelle's interconnectivity. In this perspective, we will (i) summarize the current knowledge on the mitochondrial crosstalk within cell(s) or tissue(s) in health and disease, with a particular focus on neurodegenerative disorders, (ii) discuss how different large-scale and targeted approaches could be used to characterize the different levels of mitochondrial social complexity, and (iii) consider how investigating the different expression patterns of mitochondrial proteins in different cell types/tissues could represent an important step forward in depicting the distinctive architecture of inter-organelle communication.

Fig. 1. Mitochondrial protein expression in cells and tissues.

A Number of proteins downloaded from the UniProt Database pertaining to eight different cytoplasmic compartments. B Chart representing the number of proteins localizing only in the mitochondrion or also in other cytoplasmic compartments. C Heatmap representing the expression of 1275 UniProt mitochondrial proteins according to the TISSUES database. Yellow color is used for highly expressed mitochondrial proteins, while blue for the ones expressed at lower levels. Black is used to highlight the proteins not expressed in that tissue (i.e., no value in the TISSUES database—see Supplementary Table 3). D and E Venn diagrams representing the total mitochondrial proteins (D, all expression values) or the mitochondrial proteins highly expressed (E, expression value greater than 2.5) in the muscle vs. nervous system, according to the TISSUES database (see Supplementary Table 3).

Fig. 2. Global approaches to decipher inter-organelle communication.

A Application and integration of high-throughput approaches for the spatio-temporal characterization of the cytoplasmic organelle crosstalk in different cell lines. B Data can be collected from the steps indicated above (A) to create a database that will allow the comparison of the genetic interactions and proteomics profiles among different cell lines.