The role of iron in mitochondrial function

Abstract

Background

Iron is an essential element for life, as it is a cofactor for enzymes involved in many metabolic processes, but it can also be harmful, since its excess is thought to enhance the production of reactive oxygen species and induce oxidative damage. Iron is transformed into its biologically available form in the mitochondrion by the iron–sulfur (Fe/S) cluster and heme synthesis pathways. During the past decade, substantial progress has been made in the elucidation of iron-linked mechanisms that occur in the mitochondrion, demonstrating the crucial role played by this organelle in maintaining cellular iron homeostasis.

General Significance

This review summarizes current knowledge of the mechanisms underlying iron trafficking in mitochondria and how it is handled inside the organelle. Relevant updates with regard to the Fe/S cluster and heme biosynthetic pathways, as well as the relationship between mitochondrial iron homeostasis impairment and related diseases, are also discussed.

Introduction

The main function of mitochondria is traditionally linked to energy supply for all cell compartments. However, besides this important function, these organelles exhibit many other activities that are fundamental for cell life. They generate the regulators of cellular redox potential, such as superoxide anion, hydrogen peroxide, nitric oxide, peroxynitrite etc., which control proteolysis, activation of transcription, cell metabolism, and differentiation [1]. They are responsible for the synthesis of important compounds like steroids, heme, and iron–sulfur clusters [2], [3], [4]. With their filamentous structure they transport, in addition to energy, signaling molecules and lipophilic compounds into the cell [2]. Mitochondria also play an important role in Ca²⁺ signaling and regulation of apoptotic cell death [5]. Thus, they are able to determine either the development or death of the cell [2].

Transition metal ions are required for many aspects of mitochondrial physiology and, among them, iron is one of the most abundant [6]. In fact, the mitochondrion is the site where iron is transformed into its bioactive form by the heme and iron–sulfur cluster (ISC or Fe/S) biosynthetic pathways [2], [7]. These cofactors are responsible for the activity of several enzymes involved in many metabolic reactions [8], [9], [10]. Thus, this organelle is a major user of cellular iron, plays a central role in iron metabolism and, similarly to the cell, relies on iron transport, storage, and regulatory proteins to maintain iron homeostasis [11]. Iron transport mechanisms across mitochondrial membranes have evolved to satisfy mitochondrial iron requirements and preserve the balance of the cytosolic compartment [11], [12]. Furthermore, since mitochondria are the major site of oxygen consumption and iron is also a potent inducer of ROS formation, the simultaneous presence of oxygen and iron may be detrimental to the organelle. Therefore, the mitochondrial iron level must be tightly regulated to avoid iron-dependent damage and maintain mitochondrial functionality. These control systems have not yet been completely elucidated, and the forms of iron are present and how they are handled in the mitochondrion remain uncertain. However, the importance of these mechanisms is highlighted by the finding that alterations in mitochondrial iron homeostasis lead to pathological phenotypes and cell death [4], [11]. During recent years, the availability of cellular and animal models has been a valuable tool to identify new iron proteins and elucidate some of the processes involved in mitochondrial iron homeostasis.

This review briefly summarizes our current understanding, as well as more recent findings in the field. We will focus on the description of known mitochondrial iron transport systems and iron-dependent biosyntheses; we will also discuss some hypotheses about iron pool maintenance inside the mitochondria and the relationship between mitochondrial iron misregulation and disease.