bims-mitrat 2024-12-29 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2024–12–29
ten papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Intercellular Mitochondrial transfer: Therapeutic implications for energy metabolism in heart failure.
JZL-184 Alleviate Neurological Impairment through Regulation of Mitochondrial Transfer and Lipid Droplet Accumulation after Cardiac Arrest.
Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
Mitochondrial tRNA modifications: functions, diseases caused by their loss, and treatment strategies.
How crosstalk between mitochondria, lysosomes, and other organelles can prevent or promote dry age-related macular degeneration.
Extracellular Mitochondria Exacerbate Retinal Pigment Epithelium Degeneration in Diabetic Retinopathy.
The mitochondrial and cytoplasmic superoxide anion imbalance trigger the expression of certain cellular aging markers in HaCaT keratinocytes.
Aerobic exercise timing affects mitochondrial dynamics and insulin resistance by regulating the circadian clock protein expression and NAD+-SIRT1-PPARα-MFN2 pathway in the skeletal muscle of high-fat-diet-induced diabetes mice.
Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.
Physical Activity Correlates With Skeletal Muscle MRI Findings in Individuals With Duchenne Muscular Dystrophy.

Pharmacol Res. 2024 Dec 20. pii: S1043-6618(24)00500-0. [Epub ahead of print]211 107555

Intercellular Mitochondrial transfer: Therapeutic implications for energy metabolism in heart failure.

Huan He, Weiwei Huang, Zigang Pan, Lingjun Wang, Zhongqi Yang, Zixin Chen.

  Heart failure (HF) remains one of the leading causes of high morbidity and mortality globally. Impaired cardiac energy metabolism plays a critical role in the pathological progression of HF. Various forms of HF exhibit marked differences in energy metabolism, particularly in mitochondrial function and substrate utilization. Recent studies have increasingly highlighted that improving energy metabolism in HF patients as a crucial treatment strategy. Mitochondrial transfer is emerging as a promising and precisely regulated therapeutic strategy for treating metabolic disorders. This paper specifically reviews the characteristics of mitochondrial energy metabolism across different types of HF and explores the modes and mechanisms of mitochondrial transfer between different cell types in the heart, such as cardiomyocytes, fibroblasts, and immune cells. We focused on the therapeutic potential of intercellular mitochondrial transfer in improving energy metabolism disorders in HF. We also discuss the role of signal transduction in mitochondrial transfer, highlighting that mitochondria not only function as energy factories but also play crucial roles in intercellular communication, metabolic regulation, and tissue repair. This study provides new insights into improving energy metabolism in heart failure patients and proposes promising new therapeutic strategies.

Keywords:  Cardiomyocyte repair; Energy metabolism; Heart failure; Mitochondrial transfer; Regenerative therapy

DOI:  https://doi.org/10.1016/j.phrs.2024.107555
Mol Neurobiol. 2024 Dec 24.

JZL-184 Alleviate Neurological Impairment through Regulation of Mitochondrial Transfer and Lipid Droplet Accumulation after Cardiac Arrest.

Qiang Zhang, Chenyu Zhang, Yuanzheng Lu, Haohong Zhan, Bo Li, Hongyan Wei, Yilin Yang, Liaoxing Liao, Chao Lan, Chunlin Hu.

  Astrocytes are abundant glial cells in the central nervous system (CNS) that play important roles in brain injury following cardiac arrest (CA). Following brain ischemia, astrocytes trigger endogenous neuroprotective mechanisms, such as fatty acid transport. Lipid droplets (LDs) are cellular structures involved in neutral lipid storage and play essential roles in many biological processes. However, whether lipid droplet metabolism is related to the neurological prognosis after CA remains unclear. JZL-184 is a selective irreversible inhibitor of monoacylglycerol lipase (MAGL), and previous investigations revealed that JZL-184 confers neuroprotection in the brain following stroke. However, further investigations are warranted to explore the effect and mechanism of JZL-184 after CA. Here, we reveal that JZL-184 is neuroprotective after cardiac arrest, as it alleviates astroglial activation by upregulating the expression of transforming growth factor beta 1 (TGF-β1), promotes the transfer of mitochondria from astrocytes to neurons in the astrocyte‒neuron coculture system, and reduces lipid droplet accumulation in neurons. Mechanistically, this protective effect depends on the downstream genes DUSP4 and Rab27b. This study provides additional insights into strategies for inhibiting neurological impairment and suggests a potential therapeutic target after cardiac arrest.

Keywords:  Astrocyte; Cardiac arrest; Lipid droplets; Mitochondria transfer

DOI:  https://doi.org/10.1007/s12035-024-04633-3
Free Radic Biol Med. 2024 Dec 18. pii: S0891-5849(24)01147-X. [Epub ahead of print]227 619-628

Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.

Yiwei Feng, Zhijian Rao, Xu Tian, Yi Hu, Liantian Yue, Yifan Meng, Qiuling Zhong, Wei Chen, Wenlong Xu, Haoran Li, Yingjia Hu, Rengfei Shi.

  The mitochondrial open reading frame of 12S rRNA-c (MOTS-c) is a biologically active mitochondria-derived peptide. However, the relationship between MOTS-c, skeletal muscle mitochondrial function, and endurance exercise adaptations is unknown. Here, we tested indices such as maximal oxygen uptake and serum MOTS-c levels in marathon runners and sedentary subjects. In addition, we tested aerobic exercise capacity, skeletal muscle mitochondrial respiration rate, and serum MOTS-c levels in mice subjected to long-term endurance training groups and sedentary groups. Our results indicated a close association between serum MOTS-c levels and aerobic exercise capacity. Circulating MOTS-c levels are expected to be an important indicator for predicting aerobic exercise capacity and assessing body fat status, endurance training load, and physical function. More importantly, we found that endurance training may enhance the mitochondrial respiratory function of skeletal muscle by promoting the secretion of MOTS-c and activating the AMPK/PGC-1α pathway.

Keywords:  Exercise; Mitochondria; Mitochondrial-derived peptides; Skeletal muscle; The mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-C)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.038
RNA. 2024 Dec 24. pii: rna.080257.124. [Epub ahead of print]

Mitochondrial tRNA modifications: functions, diseases caused by their loss, and treatment strategies.

Takeshi Chujo, Kazuhito Tomizawa.

  Mitochondrial tRNA (mt-tRNA) modifications play pivotal roles in decoding and sustaining tRNA stability, thereby enabling synthesis of essential respiratory complex proteins in mitochondria. Consequently, loss of human mt-tRNA modifications caused by mutations in the mitochondrial or nuclear genome can cause life-threatening mitochondrial diseases such as encephalopathy and cardiomyopathy. In this article, we first provide a comprehensive overview of the functions of mt-tRNA modifications, the responsible modification enzymes, and the diseases caused by loss of mt-tRNA modifications. We then discuss progress and potential strategies to treat these diseases, including taurine supplementation for MELAS patients, targeted deletion of mtDNA variants, and overexpression of modification-related proteins. Finally, we discuss factors that need to be overcome to cure 'mitochondrial tRNA modopathies'.

Keywords:  MELAS; mitoTALEN; mitochondrial disease; tRNA modification; tRNA modopathy

DOI:  https://doi.org/10.1261/rna.080257.124
Exp Eye Res. 2024 Dec 22. pii: S0014-4835(24)00441-X. [Epub ahead of print]251 110219

How crosstalk between mitochondria, lysosomes, and other organelles can prevent or promote dry age-related macular degeneration.

Aparna Lakkaraju, Patricia Boya, Marie Csete, Deborah A Ferrington, James B Hurley, Alfredo A Sadun, Peng Shang, Ruchi Sharma, Debasish Sinha, Marius Ueffing, Susan E Brockerhoff.

  Organelles such as mitochondria, lysosomes, peroxisomes, and the endoplasmic reticulum form highly dynamic cellular networks and exchange information through sites of physical contact. While each organelle performs unique functions, this inter-organelle crosstalk helps maintain cell homeostasis. Age-related macular degeneration (AMD) is a devastating blinding disease strongly associated with mitochondrial dysfunction, oxidative stress, and decreased clearance of cellular debris in the retinal pigment epithelium (RPE). However, how these occur, and how they relate to organelle function both with the RPE and potentially the photoreceptors are fundamental, unresolved questions in AMD biology. Here, we report the discussions of the "Mitochondria, Lysosomes, and other Organelle Interactions" task group of the 2024 Ryan Initiative for Macular Research (RIMR). Our group focused on understanding the interplay between cellular organelles in maintaining homeostasis in the RPE and photoreceptors, how this could be derailed to promote AMD, and identifying where these pathways could potentially be targeted therapeutically.

Keywords:  Bioenergetics; Oxidative stress; Photoreceptors; Retinal pigment epithelium; Therapeutics

DOI:  https://doi.org/10.1016/j.exer.2024.110219
Diabetes. 2024 Dec 23. pii: db240040. [Epub ahead of print]

Extracellular Mitochondria Exacerbate Retinal Pigment Epithelium Degeneration in Diabetic Retinopathy.

Keiichi Nishikawa, Tomoaki Murakami, Miyo Yoshida, Noriko Terada, Kenji Ishihara, Yuki Mori, Shinji Ito, Akitaka Tsujikawa.

Advances in fundus imaging are revealing disruptions in the neurovascular unit in diabetic retinopathy (DR). In the era of anti-VEGF treatment, a thorough characterization of neurodegeneration is imperative until DR patients are sufficiently cured. Here we demonstrate that extracellular mitochondria exacerbate retinal pigment epithelium (RPE) degeneration and inflammation in DR. Extracellular mitochondria increased in the vitreous of DR patients and were associated with visual impairment but not with proliferative diabetic retinopathy or diabetic macular edema. Animal experiments demonstrated detrimental effects of extracellular mitochondria on RPE and photoreceptors. Lysosomal cell death induced by extracellular mitochondria in RPE cells required mitochondrial DNA but not its pattern recognition receptors. Furthermore, biochemical screening identified candidates for DNA receptors. Among them, DNA-dependent protein kinase was necessary for extracellular mitochondria-induced cell death in both in vitro and in vivo experiments. Extracellular mitochondria further induced IL-1β and TNF-α expression in RPE cells in a Toll-like receptor 9 dependent manner. RNA sequencing suggested that extracellular mitochondria exacerbate inflammation by promoting the proliferation and migration of macrophages, at least in part. In summary, extracellular mitochondria are designated as a novel exacerbating factor of RPE degeneration in DR.

DOI: https://doi.org/10.2337/db24-0040
Biogerontology. 2024 Dec 26. 26(1): 31

The mitochondrial and cytoplasmic superoxide anion imbalance trigger the expression of certain cellular aging markers in HaCaT keratinocytes.

Nathalia Cardoso de Afonso Bonotto, Ivana Beatrice Mânica da Cruz, Bárbara Osmarin Turra, Ana Laura Kerkhoff Escher, Fernanda Dos Santos Trombini, João Arthur B Zimmermann, Verônica Farina Azzolin, Micheli Mainardi Pillat, Euler Esteves Ribeiro-Filho, Fernanda Barbisan.

  In cells, the term "cellular aging" represents a collection of biological changes that can precede the proliferative senescence states. Cells more resistant to proliferative senescence, such as the ones found in the basal layer of the epidermis, may also exhibit these aging patterns. Therefore, cellular aging events could be induced by endogenous signals named here as cellular aging triggers (CATs) components. The superoxide anion (O2⁻) could be a prime candidate for a CATs, as it is continuously produced by eukaryotic cells. To test this hypothesis, mitochondrial and cytoplasmic O2⁻ imbalances were induced in HaCaT keratinocytes using rotenone (ROT, 30 µM), which inhibits mitochondrial complex I and paraquat (PQT, 30 µM), which increases O2⁻ levels via redox cycling. ROT and PQT reduced cellular proliferation rate and elevated β-Galactosidase and transforming growth factor beta (TGF-β) levels. Furthermore, they increased the frequency of larger cells with nuclear alterations, the levels of oxidative markers, and interleukin 1β, a marker of the Senescence-Associated Secretory Phenotype (SASP). However, the mitochondrial O2⁻ imbalance caused by ROT led to more pronounced alterations compared to PQT. These findings support the hypothesis that the existence of CAT components, such as the O2⁻ anion, plays a significant role in cellular aging.

Keywords:  Cellular aging; Oxidative imbalance; Paraquat; Rotenone

DOI:  https://doi.org/10.1007/s10522-024-10168-w
J Physiol Biochem. 2024 Dec 24.

Aerobic exercise timing affects mitochondrial dynamics and insulin resistance by regulating the circadian clock protein expression and NAD+-SIRT1-PPARα-MFN2 pathway in the skeletal muscle of high-fat-diet-induced diabetes mice.

Raha Pourabdi, Fereshteh Shahidi, Mohammad Reza Tabandeh, Mojtaba Salehpour.

  The circadian clock regulates mitochondrial function and affects time-dependent metabolic responses to exercise. The present study aimed to determine the effects of aerobic exercise timing at the light-dark phase on the proteins expression of the circadian clock, mitochondrial dynamics, and, NAD+-SIRT1-PPARα axis in skeletal muscle of high-fat diet-induced diabetic mice. In this experimental study, thirty male mice were randomly assigned into two groups based on time: the early light phase, ZT3, and the early dark phase, ZT15, and three groups at each time: (1) Healthy Control (HC), (2) Diabetic Control (DC), and (3) Diabetic + Exercise (DE). Diabetes was induced by 5 weeks of feeding with a high-fat diet and Streptozotocin injection. Following confirmation of diabetes, animals underwent treadmill running at ZT3 and ZT15 for eight-weeks (5 days, 60-80 min, 50-60%Vmax). The expression of proteins of muscle aryl-hydrocarbon receptor nuclear translocator-like-1 (BMAL1), period-2 (PER2), mitofusin-2 (MFN2), dynamin-related proteins-1 (DRP-1), glucose transporter (GLUT4), sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-alpha (PPARα), and nicotinamide adenine dinucleotide (NAD+) level were analyzed in gastrocnemius muscle at both exercise times. The results showed that aerobic exercise at both times reversed the dysregulation of the diabetes-induced skeletal muscle clock by increasing the BMAL1 and PER2 protein levels. Aerobic exercise, especially at ZT15 compared to ZT3, increased GLUT4-mediated glucose uptake, and improved the diabetes-induced imbalance of mitochondrial fusion-fission by a significant increase in MFN2 protein level. Moreover, time-dependent aerobic exercise only at ZT15 increased the SIRT1 and PPARα protein levels and reduced diabetes-induced hyperglycemia. However, the aerobic exercise timing could not restore the attenuation of diabetes-induced NAD+ levels and DRP-1 protein. Our findings demonstrated that the synchronization of aerobic exercise with the circadian rhythm of NAD+-SIRT1 may boost MFN2-mediated mitochondrial fusion by activating the BMAL1-PER2-SIRT1-PPARα axis in the skeletal muscle of diabetic mice and be more effective in facilitating glycemic control and insulin resistance.

Keywords:  Aerobic exercise timing; Circadian molecular clock; Diabetes; Insulin resistance; Mitochondrial dynamics; NAD+/SIRT1; Skeletal muscle

DOI:  https://doi.org/10.1007/s13105-024-01066-3
Neurotherapeutics. 2024 Dec 26. pii: S1878-7479(24)00200-9. [Epub ahead of print] e00513

Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.

Matteo Massaro, Gherardo Baudo, Hyunho Lee, Haoran Liu, Elvin Blanco.

  Mitochondrial dysfunction is an important driver of neurodegeneration and synaptic abnormalities in Alzheimer's disease (AD). Amyloid beta (Aβ) in mitochondria leads to increased reactive oxygen species (ROS) production, resulting in a vicious cycle of oxidative stress in coordination with a defective electron transport chain (ETC), decreasing ATP production. AD neurons exhibit impaired mitochondrial dynamics, evidenced by fusion and fission imbalances, increased fragmentation, and deficient mitochondrial biogenesis, contributing to fewer mitochondria in brains of AD patients. Nuclear respiratory factor-1 (NRF1) is a regulator of mitochondrial biogenesis through its activation of mitochondrial transcription factor A (TFAM). Our hypothesis posited that NRF1 induction in neuronal cells exposed to amyloid β1-42 (Aβ1-42) would increase de novo mitochondrial synthesis and improve mitochondrial function, restoring neuronal survival. Following NRF1 messenger RNA (mRNA) transfection of Aβ1-42-treated SH-SY5Y cells, a marked increase in mitochondrial mass was observed. Metabolic programming toward enhanced oxidative phosphorylation resulted in increased ATP production. Oxidative stress in the form of mitochondrial ROS accumulation was reduced and mitochondrial membrane potential preserved. Mitochondrial homeostasis was maintained, evidenced by balanced fusion and fission processes. Ultimately, improvement of mitochondrial function was associated with significant decreases in Aβ1-42-induced neuronal death and neurite disruption. Our findings highlight the potential of NRF1 upregulation to counteract Aβ1-42-associated mitochondrial dysfunction and neurodegenerative cell processes, opening avenues for innovative therapeutic approaches aimed at safeguarding mitochondrial health in AD neurons.

Keywords:  Alzheimer's disease; Amyloid beta; Mitochondrial biogenesis; Mitochondrial dysfunction; Nuclear respiratory factor-1 (NRF1)

DOI:  https://doi.org/10.1016/j.neurot.2024.e00513
Muscle Nerve. 2024 Dec 24.

Physical Activity Correlates With Skeletal Muscle MRI Findings in Individuals With Duchenne Muscular Dystrophy.

Jaclyn Tamaroff, Nicholas Joy, Bruce Damon, Larry W Markham, Thomas Donnelly, Karry Su, Maciej S Buchowski, Kimberly Crum, James C Slaughter, Meng Xu, W Bryan Burnette, Jonathan Soslow.

   INTRODUCTION/AIMS: Skeletal muscle magnetic resonance imaging (MRI) is a validated noninvasive tool to assess Duchenne muscular dystrophy (DMD) progression. There is interest in finding DMD biomarkers that decrease the burden of clinical trial participation, such as wearable devices. Our aim was to evaluate the relationship between activity, via accelerometry, and skeletal muscle MRI, particularly T2 mapping.
METHODS: DMD children and young adults completed skeletal muscle MRI and were asked to wear an accelerometer on the dominant wrist for 7 days. MRI data included fat-suppressed transverse relaxation time (T2) mapping of the calves and longitudinal relaxation time (T1) mapping. Activity was assessed as vector magnitudes (VMs) and fraction of time (FOT) in activity groups (sedentary 1 or 2, low 1 or 2, moderate-to-vigorous physical activity (MVPA)).
RESULTS: Participants (n = 22; median age 11.4 years, 41% ambulatory) wore the accelerometer for a median of 7 days. Longer T2 in multiple lower extremity muscles was negatively correlated with VMs per minute (tibialis posterior Spearman's rho = -0.68, p < 0.001), even when accounting for age, ambulatory status, or glucocorticoid use. Longer T2 of the tibialis posterior was positively correlated with FOT in sedentary 1 (rho = 0.49, p = 0.02) and negatively correlated with FOT in higher activity levels (low 1 (rho = -0.58, p = 0.004), low 2 (rho = -0.67, p = 0.002), MVPA (rho = -0.7, p < 0.001)).
DISCUSSION: In individuals with DMD, longer T2 on skeletal muscle MRI of the calves moderately correlated with lower activity levels indicating the potential use of home accelerometry as a future clinical trial biomarker of skeletal muscle health and progression in DMD.

Keywords:  Duchenne muscular dystrophy; accelerometry; outcome measure; pediatrics; skeletal muscle MRI

DOI:  https://doi.org/10.1002/mus.28323