bims-mitrat 2025-09-28 papers

Small. 2025 Sep 27. e07970

Decoupling Half-Process Assisted Mitochondrial Transplantation via Self-Stripping pHLIP Boosts Macrophages Reprogramming for Inflammation Resolution.

Ping He, Xianghao Wu, Mingzheng Li, Kehao Liu, Yang Chen, Qianyu Zhang, Huaiyi Cheng, Yuzhou Li, Sheng Yang.

Exogenous mitochondrial transplantation holds promise for reprogramming macrophages with mitochondrial dysfunction to alleviate inflammation, yet its efficacy is hindered by poor targeting, low efficiency, or functional interference and cytotoxicity of modifiers. Herein, a convenient pH-low insertion peptides (pHLIPs)-tailored mitochondrial "decoupling transplantation" strategy (pHLIPs-PEG-TPP-Mito; PPT-Mito) is reported. In the first half, PPT-Mito can actively target the acidic cell surface of pro-inflammatory macrophages (M1) boosted by acid-sensitive pHLIPs. Subsequently, the PPT components spontaneously insert into the acidic cell membrane and self-stripped from PPT-Mito without additional intervention. This spatiotemporal separation of boosters from organelles facilitates "native" mitochondrial transplantation, while avoiding potential interference of boosters in the second half. This method significantly increases transplantation efficiency in M1 macrophages, as evidenced by a 230% increase compared to anti-inflammatory macrophages (M2)/PPT-Mito and 208% relative to M1/Mito. Consequently, PPT-Mito effectively promotes the reprogramming of M1 macrophages into M2 macrophages by remodeling energy metabolism and restoring mitochondrial function, ultimately inhibiting the inflammatory response both in vitro and in a model of periodontal inflammation. Overall, this study presents an ingenious and straightforward decoupling half-process-assisted strategy for mitochondrial transplantation, with broad potential for applications in the delivery of biological micro-organelles.

Keywords: macrophages reprogramming; mitochondrial transplantation; periodontal inflammation; the pH low insertion peptide

DOI: https://doi.org/10.1002/smll.202507970

Regen Biomater. 2025 ;12 rbaf090

Plasma-derived mitochondrial transplantation attenuates paraspinal muscle atrophy following spinal surgery.

Ikhyun Lim, Seong-Hoon Kim, Mi Jin Kim, Chang-Koo Yun, Kyunghoon Min, Yong-Soo Choi.

Paraspinal muscle atrophy (PMA) is a common complication after spinal surgery, often leading to reduced spinal stability and prolonged discomfort. While mitochondrial dysfunction has emerged as a key contributor to PMA, existing therapies do not adequately address this underlying pathophysiology. In this study, we investigated the regenerative potential of plasma-derived mitochondria (pMT) as a cell-free and autologous biomaterial to mitigate PMA. Mitochondria were isolated from human peripheral blood and confirmed to maintain their structural integrity and respiratory activity. In an in vitro model of muscle atrophy, pMT treatment improved cell viability, enhanced ATP production and restored mitochondrial function. In a rat model of surgery-induced PMA, intramuscular injections of pMT led to improved muscle morphology, including increased fiber cross-sectional area, along with reduced mechanical hypersensitivity. Transcriptomic analyses revealed that pMT transplantation modulated key pathways related to mitochondrial biogenesis and oxidative phosphorylation, while downregulating pro-apoptotic signals. These findings were corroborated by protein-level assessments showing restoration of muscle-specific markers and normalization of mitochondrial homeostasis. Taken together, this study highlights the therapeutic potential of pMT transplantation in addressing mitochondrial dysfunction and promoting muscle regeneration following spinal surgery. These findings suggest that pMT may serve as a minimally invasive, scalable and autologous regenerative approach to restore skeletal muscle integrity in clinically relevant contexts.

Keywords: laminectomy; mitochondrial transplantation; muscle regeneration; paraspinal muscle atrophy; plasma-derived mitochondria

DOI: https://doi.org/10.1093/rb/rbaf090

Redox Biol. 2025 Sep 20. pii: S2213-2317(25)00381-7. [Epub ahead of print]87 103868

Role of mitochondria transmission in ischemic stroke: Friend or foe?

Lan Yang, Xuan Wei, Zi Liao, Bei Chen, Guang Zeng, Zhigang Mei.

Ischemic stroke ranks as the second leading cause of mortality and the third disability worldwide. Disruption of energy metabolism and subsequent inflammation driven by oxidative stress constitute significant barriers to functional recovery. Proper distribution and function preservation of mitochondria are essential for maintaining energy homeostasis and modulating the inflammatory response during cerebral ischemia and reperfusion injury. Accumulating evidence indicates that both dysfunctional mitochondrial fragments and functional mitochondria undergo intracellular and intercellular transmission, significantly influencing stroke outcomes. The review details two contrasting mitochondrial processes in ischemic stroke: the release of dysfunctional mitochondrial fragments into the cytoplasm or extracellular space and the entry of functional mitochondria into damaged cells, which plays a dual role: friend or foe. The release of dysfunctional fragments activates downstream pattern recognition receptors, including the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, NLR family pyrin domain containing 3/absent in melanoma 2 inflammasome, and Toll-like receptors, triggering inflammatory cascades within the neurovascular unit and initiating cell death pathways contributing to cerebral injury. In contrast, the transfer of functional mitochondria plays a protective role by attenuating oxidative stress, preserving mitochondrial quality control, restoring neuronal energy metabolism, inhibiting apoptosis, and maintaining blood-brain barrier integrity. Therapeutic approaches that inhibit the release of dysfunctional mitochondrial fragments, enhance functional mitochondria transfer, or apply mitochondrial transplantation offer significant potential for improving outcomes in ischemic stroke.

Keywords: Dysfunctional mitochondrial fragments; Functional mitochondria transfer; Ischemic stroke; Neuroinflammation; Oxidative stress

DOI: https://doi.org/10.1016/j.redox.2025.103868