The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria.
The cellular transport of the cofactor heme and its biosynthetic intermediates such as protoporphyrin IX is a complex and highly coordinated process. To investigate the molecular details of this trafficking pathway, we created a synthetic lesion in the heme biosynthetic pathway by deleting the gene HEM15 encoding the enzyme ferrochelatase in S. cerevisiae and performed a genetic suppressor screen. Cells lacking Hem15 are respiratory-defective because of an inefficient heme delivery to the mitochondria. Thus, the biogenesis of mitochondrial cytochromes is negatively affected. The suppressor screen resulted in the isolation of respiratory-competent colonies containing two distinct missense mutations in Nce102, a protein that localizes to plasma membrane invaginations designated as eisosomes. The presence of the Nce102 mutant alleles enabled formation of the mitochondrial respiratory complexes and respiratory growth in hem15Δ cells cultured in supplemental hemin. Respiratory function in hem15Δ cells can also be restored by the presence of a heterologous plasma membrane heme permease (HRG-4), but the mode of suppression mediated by the Nce102 mutant is more efficient. Attenuation of the endocytic pathway through deletion of the gene END3 impaired the Nce102-mediated rescue, suggesting that the Nce102 mutants lead to suppression through the yeast endocytic pathway.
From the Departments of Medicine and Biochemistry, University of Utah Health Sciences Center, Salt Lake City, Utah 84132.
Hyung J
HJ
Kim
From the Departments of Medicine and Biochemistry, University of Utah Health Sciences Center, Salt Lake City, Utah 84132.
Mi-Young
MY
Jeong
the Huntsman Cancer Institute, Bioinformatics Shared Resources, Salt Lake City, Utah 84132, and.
Timothy J
TJ
Parnell
the Department of Biology and Center for Cell and Genomic Science, University of Utah, Salt Lake City, Utah 84112.
Markus
M
Babst
From the Departments of Medicine and Biochemistry, University of Utah Health Sciences Center, Salt Lake City, Utah 84132.
John D
JD
Phillips
From the Departments of Medicine and Biochemistry, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, dennis.winge@hsc.utah.edu.
Dennis R
DR
Winge
D001693:Biological Transport, Active / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D005294:Ferrochelatase / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D010101:Oxygen Consumption / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
D003598:Cytoskeletal Proteins; C091908:END3 protein, S cerevisiae; C525535:NCE102 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D006418:Heme; D005294:Ferrochelatase
Nce102; eisosomes; endocytosis; ferrochelatase; heme; membrane transport; mitochondria; mitochondrial metabolism