mitochondria

In addition to the critical role in energy metabolism, mitochondria participate in regulating ion homeostasis, redox state, cell proliferation, differentiation, and lipid synthesis. Central to these functions is the inner mitochondrial membrane (IMM), which is crucial for mitochondrial metabolism and overall function. The IMM is densely packed with proteins, comprising over 70% of its mass, that are essential for the electron transport chain, oxidative phosphorylation, energy transfer, and ion transport. The volume of the mitochondrial matrix is a pivotal factor in the structural and functional adaptation of the IMM, both under normal conditions and in response to pathological stress. Various ion transport mechanisms, particularly those involving potassium (K+) and calcium (Ca2+), regulate the osmotic pressure and volume of the matrix. Minor fluctuations in matrix volume can significantly impact the IMM’s plasticity and stimulate mitochondrial bioenergetics through multiple pathways. However, excessive matrix swelling can disrupt the structural integrity of the IMM by deforming the cristae, potentially leading to cell death mediated by mitochondria. This process is often linked to the opening of mitochondrial permeability transition pores, a phenomenon triggered by elevated matrix Ca2+ levels. Despite extensive research, the exact molecular identity of these pores remains unknown. In contrast to Ca2+, increased matrix K+ levels do not induce pore opening in the absence of elevated Ca2+ and may even provide protective effects. Despite significant research efforts, the detailed molecular mechanisms that govern matrix volume changes and IMM structural remodeling in response to energy demands and oxidative stress remain elusive. This review aims to synthesize and discuss existing studies that elucidate the regulatory mechanisms of mitochondrial matrix volume, the remodeling of the IMM, and the interplay between these processes.

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: Cellular & Molecular Mechanisms

Mitochondrial Dysfunction Overview:

  • Mitochondria play central roles in cellular energy production, immunity, and signal transduction.
  • Both primary (mutations in mitochondrial protein-encoding genes) and secondary mitochondrial diseases (mutations in non-mitochondrial genes affecting mitochondrial biology) contribute to dysfunction.
  • Evidence suggests that mitochondrial dysfunction often precedes other pathological signs in these disorders [1].

Mechanisms and Therapeutic Options:

  • Studies have investigated mechanisms of prenatal adverse outcomes related to mitochondrial dysfunction. For instance, high human chorionic gonadotropin (hCG) expression in pregnancies associated with fetal growth restriction may lead to deficits in mitochondrial DNA translation and decreased bioenergetic capacity [1].
  • Therapies targeting mitochondrial dysfunction are being explored. Notably, research on Barth syndrome (BTHS), a congenital disease linked to TAZ gene mutations affecting cardiolipin remodeling enzymes, aims to improve mitochondrial function [1].

Advances in Diagnosis and Management:

  • Our understanding of pathogenic mechanisms, disease diagnosis, and management of individuals with mitochondrial disorders has significantly progressed in the last 5 years [1].
  • Cellular mitochondrial bioenergetics analyses and brain imaging hold promise for clinical screening and detecting mitochondrial-related morbidity in conditions like fragile X-associated tremor/ataxia syndrome (FXTAS) [1].

References

  1. Giulivi, C., Zhang, K., & Arakawa, H. (2023). Recent advances and new perspectives in mitochondrial dysfunction. Scientific Reports, 13(1), 7977.

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