• Mitochondrial cristae in health and disease
  • Haleh Ehtesham,1,* Iman Halvaei,2
    1. PhD student of Tarbiat Modares University
    2. Faculty of Medicine Faculty of Tarbiat Modares University


  • Introduction: Mitochondria are oval-shaped intracellular organelles 0.5–10 μm in diameter that exist in a majority of cells and are enclosed by two membranes. Owing to their function of efficient adenosine triphosphate (ATP) generation via aerobic respiration to sustain normal cellular activities, mitochondria are often called the “powerhouse of the cell.” Mitochondrial oxidative phosphorylation (OXPHOS) is the central mechanism of energy generation and is carried out by the electron transport chain (ETC) located in the inner membrane of the mitochondria. By coupling the oxidation of reducing equivalents produced by the tricarboxylic acid (TCA) cycle and the transportation of electrons, ATP production is driven by the ETC. Mitochondria contain their own DNA (mtDNA), which encodes proteins required for OXPHOS and is replicated independent of nuclear DNA. In addition to energy production, mitochondria also engage in other processes, including reactive oxygen species (ROS) generation, calcium flux, and apoptosis, to maintain cellular homeostasis.intramitochondrial phospholipid transport by conserved Ups-Mdm35 complexes and MICOS (mitochondrial contact site and cristae organizing system) cooperatively contribute to tubular crista formation, whereas mitochondrial inner membrane fusion by Mgm1 plays a critical role in lamellar crista formation.
  • Methods: In this review, we focus on key regulators of cristae structure, including the mitochondrial contact site and cristae organizing system, optic atrophy-1, mitochondrial calcium uniporter, and ATP synthase, which function in the dynamic remodeling of cristae. We summarized their contribution to sustaining functional cristae structure and abnormal cristae morphology, including a decreased number of cristae, enlarged cristae junctions, and cristae as concentric ring structures. These abnormalities directly impact cellular respiration and are caused by dysfunction or deletion of these regulators in diseases such as Parkinson's disease, Leigh syndrome, and dominant optic atrophy. Identifying the important regulators of cristae morphology and understanding their role in sustaining mitochondrial morphology could be applied to explore the pathologies of diseases and to develop relevant therapeutic tools.
  • Results: the space between the two membranes is called the intermembrane space (IMS), and the inner membrane is divided into three specialized zones, namely the inner boundary membrane (IBM), cristae junctions (CJs), and cristae. Cristae are bag-like structures formed by the folding of IMM and provide places of residence for complexes I–V of OXPHOS. The MICOS is a complex of a plethora of proteins that staples the cristae together at the junctions.many factors participate in the regulation of cristae morphology. Depending on their location, these proteins can be divided into two categories: members located in CJs (ATP synthase) and those at the tip of cristae (MICOS, OPA1, and MICU1). When these proteins are disrupted or disturbed, their effects on mitochondrial cristae morphology differ significantly. Loss or dysfunction of proteins located in CJs leads to aberrant cristae morphology, such as wider cristae junctions, decreased cristae number, or loss of cristae. Abnormal mitochondrial cristae morphology is also observed in many diseases, including Parkinson's disease (PD), Leigh syndrome, and dominant optic atrophy (DOA), because different proteins regulate the executive functions of the cristae architecture in their pathological processes. PD is a progressive neurodegenerative disease that affects peripheral organs as well as the central nervous system. PARK is a family of genes that encodes proteins such as α-syn, LRRK2, VPS35, Parkin, PINK1, and DJ1, whose mutations lead to monogenetic PD and thus play an important role in the pathogenesis of PD.
  • Conclusion: Mitochondrial cristae are functional compartments that ultrastructure can be altered under different conditions. As mentioned above, although many mitochondrial-shaping proteins are known to be involved in cristae remodeling, a well-developed, comprehensive network of their respective roles and interactions requires further exploration. It is noteworthy that how multiple metabolic requirements of different cell types are met by the cristae remodeling. In some diseases, more than one factor is altered in mitochondrial cristae remodeling. The primary and secondary roles between them and how these roles need to be proven should be addressed in future studies.
  • Keywords: Mitochondria Cristae ultrastructure OPA1 MICOS MICU1