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Review
. 2024 May 15;9(1):124.
doi: 10.1038/s41392-024-01839-8.

Mitochondrial dysfunction: mechanisms and advances in therapy

Yao Zong #  1 , Hao Li #  2   3 , Peng Liao  2   3 , Long Chen  4 , Yao Pan  2 , Yongqiang Zheng  5 , Changqing Zhang  2 , Delin Liu  6   7 , Minghao Zheng  8 , Junjie Gao  9   10
Affiliations
Review

Mitochondrial dysfunction: mechanisms and advances in therapy

Yao Zong et al. Signal Transduct Target Ther. .

Abstract

Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The number of growing published articles or studies from 1980 to Aug 2023, based on mitochondrial medicine (pink), therapies (blue), and clinical trials (green). The publications of therapeutic targets increase following the pathfinding of mitochondria-related molecular mechanisms in many pathologies, including cardiac ischemia/reperfusion (IR) injury, stroke, and nonalcoholic steatohepatitis (NASH). Interventional clinical trials investigating the therapeutic potential of targeting mitochondrial dysfunction are also witnessing a yearly increment discernible in the volume. Data for this figure was extracted from PubMed by searching the term “mitochondri*” in combination with either “medicine”, “transplantation”, “transfer”, “administration”, “delivery”, “restore”, “rescue”, “treatment”, or “therap*”. Data of active clinical trials (recruiting, not yet recruiting, active, not recruiting, completed, enrolling by invitation, unknown status) were acquired from ClinicalTrials.gov
Fig. 2
Fig. 2
Schematic overview of mitochondrial activities. Mitochondria play a critical role in maintaining cell homeostasis by quality control, energy production, and metabolic regulation. Mitochondrial dynamics, including the processes of fission and fusion, are crucial for shaping mitochondrial structure, ensuring proper distribution across the cell, and facilitating selective clearance of damaged or dysfunctional mitochondria via degradative or secretory pathways, which plays a critical role in mitochondrial quality control. The core of mitochondrial energy production lies in the respiratory chain, fueled by the Krebs cycle and electron transport. The metabolism of fatty acids and glutamine into acetyl-CoA and alpha-ketoglutarate (α-kG), respectively, feeds into the Krebs cycle, culminating in ATP synthesis, illustrating the mitochondria’s central role in cellular energy and metabolic regulation
Fig. 3
Fig. 3
Convergence of cell signaling pathways to mitochondria. This figure delineates the integration of diverse cell signaling pathways converging on mitochondria, illustrating their central role in cellular homeostasis and stress responses. Highlighted pathways include calcium homeostasis, crucial for mitochondrial function and energy production; energy and nutrient sensing through AMPK and mTOR signaling; the innate immune response mediated by cGAS-STING, inflammasomes, and TLR9 endosomal pathways; apoptosis regulation; the unfolded protein response (UPR) as a key element of mitochondrial stress response; and the induction of cellular senescence. Together, these pathways underscore the mitochondria’s pivotal role in orchestrating cellular adaptation and survival mechanisms
Fig. 4
Fig. 4
Mechanisms of mitochondrial dysfunction in disease pathogenesis. This figure encapsulates the diverse mechanisms through which mitochondrial dysfunction contributes to common diseases. It illustrates six key dysfunctional processes: 1) Reverse Electron Transport: high Δp fuels the excessive ROS production during ischemia/reperfusion, leading to potential mtDNA damage; the accumulation of misfolded proteins and mistranslated respiratory complexes during AD and PD; imbalanced mitochondrial dynamics, mediated by ROS, Ca2+, and Aβ, affect mitochondrial morphology and function; various permeability transition pores lead to mitochondrial cargo release and initiate cell death; disrupted metabolism leading to energy imbalance and exacerbate insulin resistance; and mitochondrial genome instability resulting in altered gene expression and mitochondrial failure. Together, these mechanisms underscore the central role of mitochondria in cellular health and the etiology of various diseases, highlighting potential therapeutic targets for mitigating mitochondrial dysfunction
Fig. 5
Fig. 5
Therapeutic applications of mitochondrial and its component transplantation. This figure concludes therapeutic effects of mitochondria and associated components from different tissues and cells, to the mitochondria level (marked as grey arrows). The increased alterations in boxes are shown as up arrows while decreased alterations in boxes are shown as down arrows. Notably, though tissue level changes can vary, mitochondrial transplantation typically restores ATP production ability and reduces ROS production of damaged mitochondria. Besides, mitochondrial transplantation inhibited the intracellular try-IDO-kyn pathway, thereby improving the cognitive performance of psychiatric disorders and aging. In carbon tetrachloride (CCl4)-induced liver injury, transplanted mitochondria can increase a series of anti-oxidative enzymes to improve OXPHOS functions by triggering the UPRmt pathway. On the other hand, MSCs also repress TLR-signaling of macrophages via microRNA transfers to reduce inflammatory responses
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