Background
Mitochondrial dysfunctions are associated with a variety of pathologies, and the onset and progression of disease are accompanied by alterations in extracellular biochemical and mechanical signals. Recent studies have demonstrated that physicochemical cues, especially mechanical cues, exert pivotal roles in the organization of mitochondrial network and their metabolic functions. Therefore, understanding the mechanisms that orchestrate mitochondrial morphology and function is essential for elucidating their roles in both health and disease. In this review, we initially elucidate the critical role of mitochondrial dynamics and function in disease progression, subsequently focusing on how cells perceive extracellular mechanical signals to modulate mitochondrial dynamics and function through mechanotransduction. Last, this review explores the potential future directions, stressing that understanding mitochondrial dysfunction is crucial for developing effective therapies to improve mitochondrial function and address related diseases.

Research Progress
Mitochondrial dysfunction is characterized by abnormalities in mitochondrial fusion and fission, impaired mitochondrial oxidative phosphorylation, and abnormalities in mitochondrial autophagy. Furthermore, the transfer of mitochondria to other cells via tunneling nanotubes (TNTs) has been demonstrated to restore cellular respiratory function. This review summarizes various diseases, including neurodegenerative diseases (NDs), cardiovascular diseases (CVDs), and cancers, where different types of mitochondrial dysfunction occur. The aim is to demonstrate that targeting the regulation of mitochondrial dynamics and function may be an effective therapeutic target for improving and treating these diseases (Figure 1).

The biochemical and mechanical properties of the cellular microenvironment can change as a result of various diseases. Cells regulate their morphology, function and metabolism by sensing these changes. There is increasing evidence that mitochondrial dysfunction stems from abnormal changes in the biochemical composition and physical properties of the microenvironment. Cells perceive extracellular mechanical signals through various mechanisms, which trigger a series of biochemical reactions within the cell. These reactions ultimately influence various cellular behaviors. This process is known as mechanotransduction. Mitochondria play a crucial role in signal networks through the uptake and release of Ca²⁺ and the production of reactive oxygen species (ROS), and are involved in regulating multiple key physiological processes. Consequently, it is likely that mitochondria are involved in mechanotransduction, or that extracellular mechanical forces influence cellular behaviors by regulating mitochondrial function. Therefore, this review summarizes several mechanical transduction pathways (integrin, Piezo1/TRPV4, YAP/TAZ) and their relationship with mitochondrial dynamics and function (Figure 2) to demonstrate the important role of mitochondria in mechanical signal transduction.

Mitochondria can be transferred between cells via TNTs. This can occur between immune cells and cancer cells, fibroblasts and cancer cells, MSCs and ECs, and other homogeneous and heterogeneous cells. The donor cells transfer their healthy mitochondria via TNTs to the stimulated or damaged recipient cells. This process helps to restore the bioenergetic properties of the recipient cells, enhances cellular viability, reduces inflammatory processes, and promotes normalization of cellular functions. The subsequent section of the paper reviews the mechanisms and functions of mitochondrial transfer via TNTs (Figure 3). The results of this study underscore the significance of mitochondrial transfer in the restoration of respiration in recipient cells, the promotion of tissue repair, and the progression of tumors.

Future Prospects
Mitochondria are highly plastic and dynamic organelles that can regulate their morphology and function in response to various intracellular and extracellular stimuli. This article focuses on the specific molecular mechanisms by which intracellular and extracellular mechanical signals regulate mitochondrial morphology, function and transport. Changes in these signals are associated with diseases such as ageing, fibrosis and cancer. Therefore, investigating the mechanics of tissues and cells in relation to prevalent diseases could represent a novel therapeutic approach.

Most experiments have not involved key mechanosensitive proteins and specific signaling pathways, and other studies have been limited to particular cell lines and conditions, which makes it difficult to generalize the conclusions to other cell lines. For instance, under similar matrix stiffness conditions, normal and tumor cells exhibit different mitochondrial morphologies and functions, and the specific regulatory substrates underlying these differences require further investigation. Nevertheless, we can confidently affirm the indispensable and crucial role of mitochondrial dynamics in mechanical transduction.

Additionally, most in vitro studies are conducted under two-dimensional conditions, whereas cells in vivo exist in more complex environments and are subjected to multifaceted mechanical stimuli. Therefore, future efforts should focus on optimizing in vitro models to better reflect the true state of cells under physiological or pathological conditions. Finally, as research progresses, we must consider how to translate these mechanical signal molecules into powerful therapeutic targets for various diseases.

The complete study is accessible via DOI: 10.34133/research.0816