This Permeability Discharges Mitochondrial Membranes : A Part from the Book Chapter : Regulatory Mechanisms of Mitochondrial Volume in the Heart in Response to Physiological and Pathological Stimuli


Under normal physiological conditions, Ca2+ levels within mitochondria play a crucial role in regulating cellular energy metabolism, acting as essential messengers in signaling pathways. However, excessive elevation of mitochondrial Ca2+ levels disrupts this balance, leading to adverse outcomes such as mitochondrial fragmentation and mitochondria-mediated apoptosis. This pathological condition is particularly evident during events such as myocardial infarction and ischemia followed by reperfusion, where mitochondrial Ca2+ overload occurs. This overload is accompanied by increased ROS generation, depletion of ATP, and elevated levels of inorganic phosphate (Pi). Such disturbances significantly contribute to ischemia-reperfusion (IR) injury in the heart. The mechanism primarily involves the activation of ~2 nm diameter, non-selective, and variable-conductance mitochondrial permeability transition pores (mPTP) located in the IMM. When mPTP opens in a high-conductance mode, solutes up to a molecular mass of 1.5 kDa freely pass through the IMM. This permeability discharges mitochondrial membranes which disrupts energy metabolism and compromises the structural integrity induced by osmotic swelling. The regulation of mPTP opening is under the control of the mitochondrial chaperone protein, peptidyl-prolyl cis-trans isomerase cyclophilin D (CypD). Despite extensive research, the precise molecular composition of mPTP remains elusive, complicating the development of targeted therapies. Hence, the mPTP’s role in controlling mitochondrial volume and its importance in mitochondrial health are actively studied to this day. Researchers are particularly focused on mPTP’s therapeutic potential to mitigate ischemic damage to the heart and improve outcomes following myocardial infarction. This focus is driven by the promise of novel therapeutic interventions that can precisely manipulate mPTP activity to prevent mitochondrial dysfunction during cardiac ischemic events.

Author(s) Details:

Xavier R. Chapa-Dubocq
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Keishla M. Rodríguez-Graciani
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Joseph Capella Muniz
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Jason N. Bazil
Department of Physiology, Michigan State University, East Lansing, MI 48824-1046, USA.

Nelson Escobales
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Sabzali Javadov
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

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Recent Global Research Developments in Mitochondrial Function and Its Role in Disease

 “Recent advances and new perspectives in mitochondrial dysfunction”:

  • This editorial discusses how mitochondria play central roles in cellular energy, immunity, and signal transduction.
  • Mitochondrial dysfunction underlies various diseases, including primary (mutations in mitochondrial genes) and secondary mitochondrial diseases (mutations in non-mitochondrial genes critical for mitochondrial biology).
  • Evidence suggests that mitochondrial dysfunction often precedes other pathological signs in these disorders.
  • The collection aims to provide insights into bioenergetic deficits and potential therapeutic options [1].

“Mitochondrial homeostasis: shaping health and disease”:

  • This review focuses on mechanisms responsible for maintaining mitochondrial homeostasis.
  • It addresses both physiological and pathological functions of mitochondria [2].

“Mitochondria Lead the Way: Mitochondrial Dynamics and Function”:

  • This review evaluates recent literature on mitochondrial morphology and activity during cell shape changes in development and disease [3].

“Mitochondria-associated niches in health and disease”:

  • Discusses recent findings on mechanisms mediating communication between organelles, focusing on Ca²⁺ signaling, lipid exchange, cell death, and stress responses [4].


  1. Giulivi, C., Zhang, K., & Arakawa, H. (2023). Recent advances and new perspectives in mitochondrial dysfunction. Scientific Reports, 13(1), 7977.
  2. Li, X., Jiang, O., Chen, M. et al. Mitochondrial homeostasis: shaping health and disease. Curr Med 3, 5 (2024).
  3. Madan S, Uttekar B, Chowdhary S and Rikhy R (2022) Mitochondria Lead the Way: Mitochondrial Dynamics and Function in Cellular Movements in Development and Disease. Front. Cell Dev. Biol. 9:781933. doi: 10.3389/fcell.2021.781933
  4. Milani, M., Pihán, P., & Hetz, C. (2022). Mitochondria-associated niches in health and disease. Journal of Cell Science, 135(23), jcs259634.

To Read the Complete Chapter See Here

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