Mitochondrial Plasticity and Quality Control in Health and Disease

Editorial

02 August 2024

Editorial: Mitochondrial plasticity and quality control in health and disease

Francesca Forini

Elena Levantini

Emilia Bramanti

Filippo Maria Santorelli

, 2 more and

Milena Rizzo

1,347 views

0 citations

Editors

Milena Rizzo

Institute of Clinical Physiology, Department of Biomedical Sciences, National Research Council (CNR)

Francesca Forini

Institute of Clinical Physiology, Department of Biomedical Sciences, National Research Council (CNR)

Emilia Bramanti

Institute of Chemistry of Organometallic Compounds, Department of Chemical Sciences and Materials Technologies, National Research Council (CNR)

Elena Levantini

Pisa Research Area, National Research Council (CNR)

Filippo M Santorelli

Stella Maris Foundation (IRCCS)

Azhar Ali

Cancer Science Institute of Singapore, National University of Singapore

Vincenzo Lionetti

Sant'Anna School of Advanced Studies

Impact

(A) Simplified schematic of protein synthesis from mtDNA. mtRNA transcripts from the mtDNA coding strand are processed and translated into protein; transcripts from the noncoding strand are typically degraded. Accordingly, the RNAscope™ Dr-MT-ND5 “coding” probe reports both mtRNA and mtDNA, while the “noncoding” probe reports primarily mtDNA. (B) Workflow for mtDNA and mtRNA detection using RNAscope™ and IHC. RNAscope™ steps were carried out using the manufacturer’s protocol for the Fluorescent Multiplex v2 kit, with modifications listed in the methods section. (C) Images of zebrafish outer retina stained with a control probe against Polr2a nuclear-encoded mRNA, and a control probe against bacterial-encoded DapB mRNA. RNase treatment eliminates Polr2a mRNA signal.

Methods

14 May 2024

Spatial detection of mitochondrial DNA and RNA in tissues

Michelle Giarmarco

, 2 more and

Susan Brockerhoff

2,406 views

0 citations

Selective transcriptional/translational effects of mitochondrial-nuclear interaction regulation on myogenic differentiation. Both knockdown ClpP and using UCF101 to inhibit HtrA2 or HtrA2 inactivation in Mnd2 mouse models show that activated mitochondrial-nuclear retrograde signaling inhibits myogenic differentiation by affecting the translation of myogenic genes. Abbreviation: ISR, integrated stress response; DELE1, DAP3 binding cell death enhancer-1; GCN2, general control non-derepressible 2; PKR, Double-stranded RNA-dependent protein kinase; PERK, PKR-like ER kinase; HRI, heme-regulated eIF2α kinase; eIf2α, eukaryotic translation initiation factor 2alpha; p-eIf2α, phosphorylation of eIf2α; ATF4, activating transcription factor 4; CHOP, C/EBP homologous protein; ATF5, activating transcription factor 5; UPRmt, mitochondrial unfolded protein response; DNAJA1, DnaJ homolog subfamily A member 1; HSP70, heat shock 70 protein; HSF1, heat shock factor 1; HtrA2, High-Temperature Requirement Protein A2; ClpP, caseinolytic protease P; MyHC, myosin heavy chain; MyoG, myogenin; MyoD, myoblast determination protein 1.

Review

12 April 2024

Mitochondrial stress response and myogenic differentiation

Fu Lin

, 9 more and

Luyan Shen

4,146 views

2 citations

Diagnostic algorithm for a suspicion of mitochondrial disease.

Original Research

23 February 2024

The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study

C. Nogueira

, 21 more and

L. Vilarinho

4,176 views

5 citations

Effect of platelet-derived mitochondria on the bioenergetic properties of MDA-MB-231 cells. (A) Gene ontology results of enriched biological process identified for mitochondrial proteins related to PEVs-BCC. GO-annotation analysis was performed using STRING V11.5 gene ontology tools. Biological processes with strength >1 and false discovery rate (FDR) < 0.05 were selected. (B) Analysis of ATP content of MDA-MB-231 cells cultured with buffer or platelets for 24 h. Results were expressed as relative light units (RLU) normalized by a total number of cells. (C) Seahorse assay results of OCR for MDA-MB-231 cells cultured with buffer or platelets. MDA-MB-231 cells were co-cultured with platelets for 24 h. After that, cells were washed, reseeded, and cultured for 48 h before performing the seahorse assay. Results were normalized to µg of a total protein of each well. (D) Basal OCR of MDA-MB-231 cells cultured with buffer or platelets. (E) ATP-linked OCR of MDA-MB-231 cells cultured with buffer or platelets. (F) Flow cytometry histograms of TMRE signal in MDA-MB-231 cells after 24 h co-culture. MDA-MB-231 cells were cultured with buffer or platelets, and mitochondrial membrane potential (ΔΨm) was analyzed using TMRE dye. (G) TMRE MFI in MDA-MB-231 cells cultured with buffer or platelets. (H) Analysis of ATP content of sorted MDA-MB-231 cells cultured with buffer or platelets for 24 h. MDA-MB-231 cells were cultured with platelets previously stained with MTG. MDA-MB-231 cells positive for MTG signal were separated according to MTG intensity, retrieving two populations. Those with low MTG intensity are named MITO-Low, and those with high MTG intensity are named MITO-High. Results are expressed as RLU normalized by the total number of cells. (I) Analysis of relative mitochondrial DNA (mtDNA) levels of sorted MDA-MB-231 cells. Relative mtDNA levels were determined using quantitative PCR (qPCR) by amplifying mtDNA and nuclear DNA (ncDNA). A t-student statistical test was performed. *p < 0.05; **p < 0.01; ns = not significant.

Original Research

12 January 2024

Impact of platelet-derived mitochondria transfer in the metabolic profiling and progression of metastatic MDA-MB-231 human triple-negative breast cancer cells

Lucas Cereceda

, 3 more and

Yessia Hidalgo

Introduction: An active role of platelets in the progression of triple-negative breast cancer (TNBC) cells has been described. Even the role of platelet-derived extracellular vesicles on the migration of MDA-MB-231 cells has been reported. Interestingly, upon activation, platelets release functional mitochondria into the extracellular environment. However, the impact of these platelet-derived mitochondria on the metabolic properties of MDA-MB-231 cells remains unclear.

Methods: MDA-MB-231 and MDA-MB-231-Rho-0 cells were co-cultured with platelets, which were isolated from donor blood. Mitochondrial transfer was assessed through confocal microscopy and flow cytometry, while metabolic analyses were conducted using a Seahorse XF HS Mini Analyzer. The mito-chondrial DNA (mtDNA) copy number was determined via quantitative PCR (qPCR) following platelet co-culture. Finally, cell proliferation and colony formation assay were performed using crystal violet staining.

Results and Discussion: We have shown that platelet-derived mitochondria are internalized by MDA-MB-231 cells in co-culture with platelets, increasing ATP production, oxygen (O₂) consumption rate (OCR), cell proliferation, and metabolic adaptability. Additionally, we observed that MDA-MB-231 cells depleted from mtDNA restore cell proliferation in uridine/pyruvate-free cell culture medium and mitochondrial O₂ consumption after co-culture with platelets, indicating a reconstitution of mtDNA facilitated by platelet-derived mitochondria. In conclusion, our study provides new insights into the role of platelet-derived mitochondria in the metabolic adaptability and progression of metastatic MDA-MB-231 TNBC cells.

6,441 views

10 citations

Original Research

07 November 2023

Cardioprotective effects of Moku-boi-to and its impact on AngII-induced cardiomyocyte hypertrophy

Hideaki Tagashira

, 6 more and

Tomohiro Numata

2,633 views

3 citations

Review

06 November 2023

Mitochondrial quality control in health and cardiovascular diseases

Asli E. Atici

, 1 more and

Magali Noval Rivas

10,108 views

26 citations

Review

30 October 2023

Mesenchymal stromal/stem cells and bronchopulmonary dysplasia

Shuqing Zhang

, 3 more and

Dongmei Yue

Bronchopulmonary dysplasia (BPD) is a common complication in preterm infants, leading to chronic respiratory disease. There has been an improvement in perinatal care, but many infants still suffer from impaired branching morphogenesis, alveolarization, and pulmonary capillary formation, causing lung function impairments and BPD. There is an increased risk of respiratory infections, pulmonary hypertension, and neurodevelopmental delays in infants with BPD, all of which can lead to long-term morbidity and mortality. Unfortunately, treatment options for Bronchopulmonary dysplasia are limited. A growing body of evidence indicates that mesenchymal stromal/stem cells (MSCs) can treat various lung diseases in regenerative medicine. MSCs are multipotent cells that can differentiate into multiple cell types, including lung cells, and possess immunomodulatory, anti-inflammatory, antioxidative stress, and regenerative properties. MSCs are regulated by mitochondrial function, as well as oxidant stress responses. Maintaining mitochondrial homeostasis will likely be key for MSCs to stimulate proper lung development and regeneration in Bronchopulmonary dysplasia. In recent years, MSCs have demonstrated promising results in treating and preventing bronchopulmonary dysplasia. Studies have shown that MSC therapy can reduce inflammation, mitochondrial impairment, lung injury, and fibrosis. In light of this, MSCs have emerged as a potential therapeutic option for treating Bronchopulmonary dysplasia. The article explores the role of MSCs in lung development and disease, summarizes MSC therapy’s effectiveness in treating Bronchopulmonary dysplasia, and delves into the mechanisms behind this treatment.

4,045 views

12 citations

Defects in protrusion formation and germ cell polarity in sod2 KO and neomycin-treated embryos. Analysis of (A, D) the number of blebs in PGCs per minute and (B, E) the proportion of blebs at the cell back. In graphs A and B, MZsod2STOP31 embryos were injected with control RNA or with RNA directing Sod2 expression to the germ cells (see Methods); the same cells were analyzed in panels A and (B). In graphs D and E, wild-type embryos were treated with DMSO or with neomycin; the same cells were analyzed in panels D and (E). (C, F) Snapshots from the representative time-lapse movies (movies S1 and S2) analyzed in (A,B,D, E). Yellow asterisks point at blebs at the rear of cells. n - the number of PGCs analyzed. One PGC per embryo was imaged and analyzed. **p < 0.01, *p < 0.05, were calculated by Student’s t-test.

Original Research

26 October 2023

The mitochondrial protein Sod2 is important for the migration, maintenance, and fitness of germ cells

Katsiaryna Tarbashevich

, 3 more and

Erez Raz

1,776 views

1 citations

Review

03 August 2023

Targeting mitochondrial dynamics proteins for the treatment of doxorubicin-induced cardiotoxicity

Rui Chen

, 2 more and

Yuquan He

The mechanics of mitochondrial fission and fusion. Schematic representation of mitochondrial fusion and fission machinery and related cell function. (A) Mitochondrial dynamics-associated key mediators including pro-fission proteins (DRP1, FIS1, MFF, MiD49, MiD51, and MTF18) and pro-fusion proteins (MFN1, MFN2, and OPA1). (B) Mitochondrial fission is mainly regulated by the key player DRP1, OMM receptors (MFF, MiD49, MiD51 and FIS1), which are responsible for the recruitment of DRP1 from the cytosol to mitochondria. And ER wraps mitochondria and identifies the fission site, where DRP1 oligomerizes and induces mem-brane constriction. (C) Mitochondrial fusion relies on MFN1 and MFN2 located on the OMM to tether the OMMs of mitochondria, and on OPA1 to mediate fusion of IMM. (D) Mitochondrial fate is regulated by fission and fusion to adapt mitochondrial morphology to different stresses. Fission constricts and severs one mitochondrion to daughter mitochondria for cell division or fragmented mitochondria for removal by mitophagy and renewal by fusion into an elongated organelle.

Doxorubicin (DOX) is an extensively used chemotherapeutic agent that can cause severe and frequent cardiotoxicity, which limits its clinical application. Although there have been extensive researches on the cardiotoxicity caused by DOX, there is still a lack of effective treatment. It is necessary to understand the molecular mechanism of DOX-induced cardiotoxicity and search for new therapeutic targets which do not sacrifice their anticancer effects. Mitochondria are considered to be the main target of cardiotoxicity caused by DOX. The imbalance of mitochondrial dynamics characterized by increased mitochondrial fission and inhibited mitochondrial fusion is often reported in DOX-induced cardiotoxicity, which can result in excessive ROS production, energy metabolism disorders, cell apoptosis, and various other problems. Also, mitochondrial dynamics disorder is related to tumorigenesis. Surprisingly, recent studies show that targeting mitochondrial dynamics proteins such as DRP1 and MFN2 can not only defend against DOX-induced cardiotoxicity but also enhance or not impair the anticancer effect. Herein, we summarize mitochondrial dynamics disorder in DOX-induced cardiac injury. Furthermore, we provide an overview of current pharmacological and non-pharmacological interventions targeting proteins involved in mitochondrial dynamics to alleviate cardiac damage caused by DOX.

4,551 views

17 citations

Brief Research Report

26 June 2023

Regulation of mitochondrial morphology and cristae architecture by the TLR4 pathway in human skeletal muscle

Mauricio Castro-Sepulveda

, 4 more and

Hermann Zbinden-Foncea

2,864 views

4 citations

Original Research

06 June 2023