Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase
Jonathan V. Dietz,
Mathilda M. Willoughby,
Robert B. Piel, III,
Teresa A. Ross,
Iryna Bohovych,
Hannah G. Addis,
Jennifer L. Fox,
William N. Lanzilotta,
Harry A. Dailey,
James A. Wohlschlegel,
Amit R. Reddi,
Amy E. Medlock,
Oleh Khalimonchuk
Affiliations
Jonathan V. Dietz
Department of Biochemistry, University of Nebraska, Lincoln, NE, 68588, USA
Mathilda M. Willoughby
School of Chemistry and Biochemistry and School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA; Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA
Robert B. Piel, III
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA
Teresa A. Ross
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA
Iryna Bohovych
Department of Biochemistry, University of Nebraska, Lincoln, NE, 68588, USA
Hannah G. Addis
Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC, 29424, USA
Jennifer L. Fox
Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC, 29424, USA
William N. Lanzilotta
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA
Harry A. Dailey
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA; Department of Microbiology, University of Georgia, Athens, GA, 30602, USA
James A. Wohlschlegel
Department of Biological Chemistry, University of California, Los Angeles, CA, 90095, USA
Amit R. Reddi
School of Chemistry and Biochemistry and School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA; Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA
Amy E. Medlock
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA; Augusta University/University of Georgia Medical Partnership, Athens, GA, 30602, USA
Oleh Khalimonchuk
Department of Biochemistry, University of Nebraska, Lincoln, NE, 68588, USA; Nebraska Redox Biology Center, University of Nebraska, Lincoln, NE, 68588, USA; Fred & Pamela Buffett Cancer Center, Omaha, NE, 68198, USA; Corresponding author. Department of Biochemistry, University of Nebraska, Lincoln, NE, 68588, USA.
Heme is an essential cofactor required for a plethora of cellular processes in eukaryotes. In metazoans the heme biosynthetic pathway is typically partitioned between the cytosol and mitochondria, with the first and final steps taking place in the mitochondrion. The pathway has been extensively studied and its biosynthetic enzymes structurally characterized to varying extents. Nevertheless, understanding of the regulation of heme synthesis and factors that influence this process in metazoans remains incomplete. Therefore, we investigated the molecular organization as well as the physical and genetic interactions of the terminal pathway enzyme, ferrochelatase (Hem15), in the yeast Saccharomyces cerevisiae. Biochemical and genetic analyses revealed dynamic association of Hem15 with Mic60, a core component of the mitochondrial contact site and cristae organizing system (MICOS). Loss of MICOS negatively impacts Hem15 activity, affects the size of the Hem15 high-mass complex, and results in accumulation of reactive and potentially toxic tetrapyrrole precursors that may cause oxidative damage. Restoring intermembrane connectivity in MICOS-deficient cells mitigates these cytotoxic effects. These data provide new insights into how heme biosynthetic machinery is organized and regulated, linking mitochondrial architecture-organizing factors to heme homeostasis.
