Dual targeting of mitochondrial proteins: Mechanism, regulation and function

Abstract

One solution found in evolution to increase the number of cellular functions, without increasing the number of genes, is distribution of single gene products to more than one cellular compartment. It is well documented that in eukaryotic cells, molecules of one protein can be located in several subcellular locations, a phenomenon termed dual targeting, dual localization, or dual distribution. The differently localized proteins are coined in this review "echoforms" indicating repetitious forms of the same protein (echo in Greek denotes repetition) distinctly placed in the cell. This term replaces the term to "isoproteins" or "isoenzymes" which are reserved for proteins with the same activity but different amino acid sequences. Echoforms are identical or nearly identical, even though, as referred to in this review may, in some cases, surprisingly have a totally different function in the different compartments. With regard to mitochondria, our operational definition of dual targeted proteins refers to situations in which one of the echoforms is translocated through/into a mitochondrial membrane. In this review we ask how, when and why mitochondrial proteins are dual localized in the cell. We describe mechanisms of dual targeting of proteins between mitochondria and other compartments of the eukaryotic cell. In particular, we have paid attention to situations in which dual localization is regulated in time, location or function. In addition, we have attempted to provide a broader view concerning the phenomenon of dual localization of proteins by looking at mechanisms that are beyond our simple definition of dual targeting. This article is part of a Special Issue entitled Protein translocation across or insertion into membranes.

LL-37-induced host cell cytotoxicity depends on cellular expression of the globular C1q receptor (p33)

“…While the molecular mechanisms are not completely understood, it appears that shuttling of p33 between the cytosol and mitochondria or the nucleus is essential in these processes [42,43]. Dual or multifold intracellular targeting of proteins with specific localization sequences is an emerging field of research [44,45] and several mechanisms have been proposed to explain this phenomenon. These include, for instance, different or several translation products, multiple mRNAs or membrane permeabilization.…”

Spatial Distribution of Cellular Function: The Partitioning of Proteins between Mitochondria and the Nucleus in MCF7 Breast Cancer Cells

“…[38][39][40][41][42]70,[85][86][87] In the following we discuss three topics: (a) the use of sucrose gradient fractionation in MS-based proteomics to obtain data about subcellular spatial distribution of proteins, (b) how the observed distributions might be related to MCF7 cells as cancer cells, and (c) the implications of our results for how such spatial distributions may relate to overall control of cellular function.…”

“…Now it seems necessary to also reexamine the corollary that one protein gives one subcellular location gives one function. 38,70,87 In doing so we might remember that cells seem to have a high degree of plasticity and that, for example, in protists there can be major differences in the organization of subcellular location/function. 106 We might also take note of complex systems theory and begin to consider whether the functional diversity, partial overlap with other processes, highly diverse networks and spatial distribution characteristics may be a reflection of the need for robustness in complex systems.…”

“…For example, mechanisms are known that locate mRNAs for some mitochondrial proteins to the mitochondrial outer membrane surface, 68,69 and some mitochondrial proteins seem to be at least partially cotranslationally inserted into mitochondria. 70 More detailed examination of the distribution between the nucleus and mitochondria of individual proteins from cytosolic protein groups suggests that some partition as welldefined complexes. For example, in the {m&n} subset the F-actin capping protein (Table 4) shows strong correlation between nuclear and mitochondrial counts, with the slope of the linear correlation close to the ratio of total counts in each location.…”

The Peroxisomal NAD Carrier from Arabidopsis Imports NAD in Exchange with AMP

“…Further yeast candidates for the peroxisomal NAD transport are the two mitochondrial Ndt proteins (Todisco et al, 2006). These carriers are able to specifically import NAD and might be dual-targeted to yeast peroxisomes, since several mitochondrial proteins have been also found in peroxisomes Ast et al, 2013;Carrie et al, 2009;Yogev and Pines, 2011). Ndt1p has been demonstrated by GFP fusion to be located to mitochondria (Todisco et al, 2006), whereas the mitochondrial localization of Ndt2p has not been experimentally validated.…”