With the completion of a comprehensive genome-wide screen the number of genes implicated in mitochondrial function and morphology has been more than doubled. The systematic approach enabled the identification of a number of components that have been missed by classical approaches that typically were based on the screening of collections of temperature-sensitive mutants generated by random mutagenesis (Hermann and Shaw, 1998
). Most notably, the systematic screening of a deletion mutant library revealed a number of mdm
mutants lacking an obvious growth defect (e.g., mdm30
) that presumably could not be easily identified by conventional genetic screens. This illustrates the power of the genomic approach that should turn out to be equally fruitful also for the study of many other cellular processes.
What might be the cellular roles of the newly discovered MDM
genes? Only in two cases the predicted protein sequence is suggestive of a function. MDM30
encodes a protein of unknown function that contains an F-box, a motif involved in targeting of proteins to ubiquitin-dependent proteolysis (Patton et al., 1998
). Furthermore, high-throughput two-hybrid analysis (Uetz et al., 2000
) identified Mdm30p as a possible interaction partner of Cdc53p and Skp1p, two core components of the SCF (Skp1p-cullin-F-box) complexes, which target proteins for ubiquitin-dependent degradation (Skowyra et al., 1997
). Because it is known that protein ubiquitination is important for mitochondrial inheritance (Fisk and Yaffe, 1999
), we propose that Mdm30p is a novel factor involved in this process. MDM38
encodes a protein that shares homology with a mitochondrial protein of unknown function of Drosophila
, the CG4589 gene product (Caggese et al., 1999
). This protein is a calcium-binding protein that contains two EF hand calcium binding domains. It will be interesting to see whether Mdm38p plays a role in calcium homeostasis of mitochondria and thereby influences organellar morphology.
During the past decade, several genetic and morphological screens have revealed a number of important components involved in mitochondrial inheritance, yet many processes determining mitochondrial behavior are not well understood. These include the machinery connecting mitochondria to the actin cytoskeleton (Simon et al., 1995
; Boldogh et al., 1998
), proteins cooperating with Fzo1p (Hermann et al., 1998
; Rapaport et al., 1998
; Fritz et al., 2001
) or Ugo1p (Sesaki and Jensen, 2001
) in mediating mitochondrial membrane fusion, and components shaping the internal structure of mitochondria (Wong et al., 2000
). The proteins encoded by the majority of the newly identified MDM
genes do not share homology to other known proteins. Their varied and striking mutant phenotypes suggest that they are important players in a number of different processes contributing to the morphogenesis of mitochondria. The relatively small number of newly identified components suggests that the screen was rather specific. It is important to note, however, that our results were obtained with null alleles. Thus, it cannot be excluded that some of the newly identified genes perform primary functions not directly related to mitochondrial morphogenesis and that the mitochondrial phenotypes might be due to indirect effects accumulating in the deletion strains. It will be a major challenge for the future to establish the molecular functions of the newly discovered proteins and to unravel the interactions among the components of mitochondrial behavior. These studies will certainly improve our understanding of the mechanisms that shape this complex double membrane-bounded organelle.
The results of the screen suggest that most of the proteins constituting the core machinery of mitochondrial morphogenesis uniquely affect this organelle. With the exception of the dynamin-related proteins Dnm1p and Mgm1p, none of the key components of mitochondrial inheritance shares homology with any other known protein involved in membrane trafficking events of other organelles. Vice versa, besides Num1p, none of the components involved in biogenesis of other organelles was found to be essential for normal mitochondrial structure. It appears that Nature invented an entirely new machinery of organelle maintenance after the endosymbiotic ancestors of mitochondria entered the eukaryotic cell.