Mitochondrial contact site and cristae organizing system (MICOS) machinery supports heme biosynthesis by enabling optimal performance of ferrochelatase

Redox Biology

Amit R. Reddi¹  Robert B. Piel, III²  James A. Wohlschlegel³  Harry A. Dailey³  Iryna Bohovych³  Teresa A. Ross³  Jonathan V. Dietz⁴  Hannah G. Addis⁴  Amy E. Medlock⁵  William N. Lanzilotta⁶  Jennifer L. Fox⁶  Oleh Khalimonchuk⁷  Mathilda M. Willoughby⁷ 

[1] Department of Microbiology, University of Georgia, Athens, GA, 30602, USA;Parker Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA;Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA;Department of Biochemistry, University of Nebraska, Lincoln, NE, 68588, USA;Department of Biological Chemistry, University of California, Los Angeles, CA, 90095, USA;Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC, 29424, USA;School of Chemistry and Biochemistry and School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA;

关键词: Mitochondria;    Heme;    MICOS;    Ferrochelatase;    Yeast;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown