Mitochondrial Transplantation Modulates Inflammation and Apoptosis, Alleviating Tendinopathy Both In Vivo and In Vitro

Abstract

Tendinopathy is a common musculoskeletal condition causing pain and dysfunction. Conventional treatment and surgical procedures for tendinopathy are insufficient; accordingly, recent research has focused on tendon-healing regenerative approaches. Tendon injuries usually occur in the hypoxic critical zone, characterized by increased oxidative stress and mitochondrial dysfunction; thus, exogenous intact mitochondria may be therapeutic. We aimed to assess whether mitochondrial transplantation could induce anti-inflammatory activity and modulate the metabolic state of a tendinopathy model. Exogenous mitochondria were successfully delivered into damaged tenocytes by centrifugation. Levels of Tenomodulin and Collagen I in damaged tenocytes were restored with reductions in nuclear factor-κB and matrix metalloproteinase 1. The dysregulation of oxidative stress and mitochondrial membrane potential was attenuated by mitochondrial transplantation. Activated mitochondrial fission markers, such as fission 1 and dynamin-related protein 1, were dose-dependently downregulated. Apoptosis signaling pathway proteins were restored to the pre-damage levels. Similar changes were observed in a collagenase injection-induced rat model of tendinopathy. Exogenous mitochondria incorporated into the Achilles tendon reduced inflammatory and fission marker levels. Notably, collagen production was restored. Our results demonstrate the therapeutic effects of direct mitochondrial transplantation in tendinopathy. These effects may be explained by alterations in anti-inflammatory and apoptotic processes via changes in mitochondrial dynamics.

Roles of Oxidative Stress in Acute Tendon Injury and Degenerative Tendinopathy—A Target for Intervention

“…The authors concluded that mitochondrial protection might protect tendon and promote tendon healing. Subsequently in the same year, one research group transplanted exogeneous intact mitochondria isolated from mesenchymal stromal cells derived from umbilical cord (UC-MSCs) to TNF-α-treated tenocytes and successfully attenuated oxidative stress, promoted mitochondrial functional recovery, restored the expression of tenogenic markers, inhibited apoptosis, and reduced the expression of pro-inflammatory markers and pNF-kB in damaged tenocytes [ 115 ]. Similarly, local injection of mitochondria isolated from L6 myoblasts to the Achilles tendon 2 weeks after collagenase-induced injury reduced the expression of apoptosis and pro-inflammatory markers, pNF-kB, MMP1 and increased collagen content 2 weeks after injection [ 115 ].…”

“…Subsequently in the same year, one research group transplanted exogeneous intact mitochondria isolated from mesenchymal stromal cells derived from umbilical cord (UC-MSCs) to TNF-α-treated tenocytes and successfully attenuated oxidative stress, promoted mitochondrial functional recovery, restored the expression of tenogenic markers, inhibited apoptosis, and reduced the expression of pro-inflammatory markers and pNF-kB in damaged tenocytes [ 115 ]. Similarly, local injection of mitochondria isolated from L6 myoblasts to the Achilles tendon 2 weeks after collagenase-induced injury reduced the expression of apoptosis and pro-inflammatory markers, pNF-kB, MMP1 and increased collagen content 2 weeks after injection [ 115 ]. Pretreatment of Achilles tenocytes with Alda-1, a selective activator of mitochondrial aldehyde dehydrogenase 2 (ALDH2), which alleviates oxidative stress and ER stress, attenuated H 2 O 2 -induced cell death, oxidative stress, mitochondrial membrane depolarization and apoptosis [ 23 ].…”

Requirements for successful mitochondrial transplantation

“…[62] Total protein measurement has been performed by bicinchoninic acid assay (BCA), Bradford, Biuret, and Lowry methods. Lee et al [30] determined the amount of isolated mitochondrial protein using the BCA method in the tendinopathy model. Huang et al [28] demonstrated that the total amount of mitochondrial protein was determined by the Bradford method on the brain ischemia model.…”

“…[28] Similarly, Sun et al [36] transplanted 750 and 1500 µg mitochondria on the acute respiratory distress syndrome model. Lee et al [30] injected 10 and 50 µg mitochondria into the Achilles tendon on the tendinopathy model, and Zhou et al [43] injected 0.2 or 0.4 mg/kg mitochondria once every day for 7 days…”

Mitochondrial Transplantation Attenuates Neural Damage and Improves Locomotor Function After Traumatic Spinal Cord Injury in Rats

“…Hence, exploring a novel strategy that effectively counteracts inflammation-induced secondary injuries is critical for treating traumatic SCI. Recently, a mitochondria-targeted treatment has emerged as a potential anti-inflammatory intervention ( Wang et al, 2019 ; Lee et al, 2021 ).…”