bims-mikwok 2022-02-06 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2022‒02‒06
nine papers selected by
Avinash N. Mukkala
University of Toronto

Mitophagy alleviates ischemia/reperfusion-induced microvascular damage through improving mitochondrial quality control.
The importance of mitochondrial quality control for maintaining skeletal muscle function across healthspan.
In-cytoplasm mitochondrial transplantation for mesenchymal stem cells engineering and tissue regeneration.
Drp1 regulates transcription of ribosomal protein genes in embryonic hearts.
The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation.
Platelet-derived respiratory-competent mitochondria transfer to mesenchymal stem cells to promote wound healing via metabolic reprogramming.
Flow-induced endothelial mitochondrial remodeling mitigates mitochondrial reactive oxygen species production and promotes mitochondrial DNA integrity in a p53-dependent manner.
TAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A.
Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.

Bioengineered. 2022 Feb;13(2): 3596-3607

Mitophagy alleviates ischemia/reperfusion-induced microvascular damage through improving mitochondrial quality control.

Dan Wu, Haizhe Ji, Wenjuan Du, Lina Ren, Geng Qian.

  The coronary arteries mainly function to perfuse the myocardium. When coronary artery resistance increases, myocardial perfusion decreases and myocardial remodeling occurs. Mitochondrial damage has been regarded as the primary cause of microvascular dysfunction. In the present study, we explored the effects of mitophagy activation on microvascular damage. Hypoxia/reoxygenation injury induced mitochondrial oxidative stress, thereby promoting mitochondrial dysfunction in endothelial cells. Mitochondrial impairment induced apoptosis, reducing the viability and proliferation of endothelial cells. However, supplementation with the mitophagy inducer urolithin A (UA) preserved mitochondrial function by reducing mitochondrial oxidative stress and stabilizing the mitochondrial membrane potential in endothelial cells. UA also sustained the viability and improved the proliferative capacity of endothelial cells by suppressing apoptotic factors and upregulating cyclins D and E. In addition, UA inhibited mitochondrial fission and restored mitochondrial fusion, which reduced the proportion of fragmented mitochondria within endothelial cells. UA enhanced mitochondrial biogenesis in endothelial cells by upregulating sirtuin 3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These results suggested that activation of mitophagy may reduce hypoxia/reoxygenation-induced cardiac microvascular damage by improving mitochondrial quality control and increasing cell viability and proliferation.

Keywords:  UA; cardiac microvascular injury; endothelial cells; hypoxia/reoxygenation; mitophagy

DOI:  https://doi.org/10.1080/21655979.2022.2027065
Am J Physiol Cell Physiol. 2022 Feb 02.

The importance of mitochondrial quality control for maintaining skeletal muscle function across healthspan.

James Sligar, Danielle A Debruin, Nicholas J Saner, Ashleigh M Philp, Andrew Philp.

  As the principal energy-producing organelles of the cell, mitochondria support numerous biological processes related to metabolism, growth and regeneration in skeletal muscle. Deterioration in skeletal muscle functional capacity with age is thought to be driven in part by a reduction in skeletal muscle oxidative capacity and reduced fatigue resistance. Underlying this maladaptive response is the development of mitochondrial dysfunction caused by alterations in mitochondrial quality control (MQC), a term encompassing processes of mitochondrial synthesis (biogenesis), remodelling (dynamics) and degradation (mitophagy). Knowledge regarding the role and regulation of MQC in skeletal muscle and the influence of ageing in this process have rapidly advanced in the last decade. Given the emerging link between ageing and MQC, therapeutic approaches to manipulate MQC to prevent mitochondrial dysfuntion during ageing hold tremendous therapeutic potential.

Keywords:  biogenesis; metabolism; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00388.2021
Bioeng Transl Med. 2022 Jan;7(1): e10250

In-cytoplasm mitochondrial transplantation for mesenchymal stem cells engineering and tissue regeneration.

Xudong Yao, Yuanzhu Ma, Wenyan Zhou, Youguo Liao, Zongsheng Jiang, Junxin Lin, Qiulin He, Hongwei Wu, Wei Wei, Xiaozhao Wang, Mikael Björklund, Hongwei Ouyang.

  Stem cell therapies are unsatisfactory due to poor cell survival and engraftment. Stem cell used for therapy must be properly "tuned" for a harsh in vivo environment. Herein, we report that transfer of exogenous mitochondria (mito) to adipose-derived mesenchymal stem cells (ADSCs) can effectively boost their energy levels, enabling efficient cell engraftment. Importantly, the entire process of exogeneous mitochondrial endocytosis is captured by high-content live-cell imaging. Mitochondrial transfer leads to acutely enhanced bioenergetics, with nearly 17% of higher adenosine 5'-triphosphate (ATP) levels in ADSCs treated with high mitochondrial dosage and further results in altered secretome profiles of ADSCs. Mitochondrial transfer also induced the expression of 334 mRNAs in ADSCs, which are mainly linked to signaling pathways associated with DNA replication and cell division. We hypothesize that increase in ATP and cyclin-dependent kinase 1 and 2 expression might be responsible for promoting enhanced proliferation, migration, and differentiation of ADSCs in vitro. More importantly, mito-transferred ADSCs display prolonged cell survival, engraftment and horizontal transfer of exogenous mitochondria to surrounding cells in a full-thickness skin defect rat model with improved skin repair compared with nontreated ADSCs. These results demonstrate that intracellular mitochondrial transplantation is a promising strategy to engineer stem cells for tissue regeneration.

Keywords:  bioenergetics; mesenchymal stem cells; mitochondrial transfer; tissue regeneration

DOI:  https://doi.org/10.1002/btm2.10250
J Cell Sci. 2022 Jan 31. pii: jcs.258956. [Epub ahead of print]

Drp1 regulates transcription of ribosomal protein genes in embryonic hearts.

Qiancong Zhao, Shun Yan, Jin Lu, Danitra J Parker, Huiying Wu, Qianchuang Sun, David K Crossman, Shanrun Liu, Qin Wang, Hiromi Sesaki, Kasturi Mitra, Kexiang Liu, Kai Jiao.

  Mitochondrial dysfunction causes severe congenital cardiac abnormalities and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect cardiogenesis poses a major barrier for the development of clinical applications that target mitochondrial deficiency induced inborn cardiomyopathies. Mitochondrial morphology, which is regulated by fission and fusion, plays a key role in determining mitochondrial activity. Dnm1l encodes a dynamin-related GTPase, Drp1, which is required for mitochondrial fission. To investigate the role of Drp1 on cardiogenesis during the embryonic metabolic shift period, we specifically inactivated Dnm1l in second heart field-derived structures. Mutant cardiomyocytes in the right ventricle (RV) displayed severe defects in mitochondrial morphology, ultrastructure, and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes, and embryonic lethality. Through characterizing this model, we reveal a novel AMPK-SIRT7-GABPB axis that relays the reduced cellular energy level to decreased transcription of ribosomal protein genes in cardiomyocytes. We therefore provide the first mouse genetic evidence to suggest that Drp1 is essential for RV development. Our research provides further mechanistic insight regarding how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.

Keywords:  Drp1; Heart development; RP gene transcription

DOI:  https://doi.org/10.1242/jcs.258956
Mol Cell. 2022 Jan 28. pii: S1097-2765(22)00008-9. [Epub ahead of print]

The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation.

Katia Cosentino, Vanessa Hertlein, Andreas Jenner, Timo Dellmann, Milos Gojkovic, Aida Peña-Blanco, Shashank Dadsena, Noel Wajngarten, John S H Danial, Jervis Vermal Thevathasan, Markus Mund, Jonas Ries, Ana J Garcia-Saez.

  BAX and BAK are key apoptosis regulators that mediate the decisive step of mitochondrial outer membrane permeabilization. However, the mechanism by which they assemble the apoptotic pore remains obscure. Here, we report that BAX and BAK present distinct oligomerization properties, with BAK organizing into smaller structures with faster kinetics than BAX. BAK recruits and accelerates BAX assembly into oligomers that continue to grow during apoptosis. As a result, BAX and BAK regulate each other as they co-assemble into the same apoptotic pores, which we visualize. The relative availability of BAX and BAK molecules thereby determines the growth rate of the apoptotic pore and the relative kinetics by which mitochondrial contents, most notably mtDNA, are released. This feature of BAX and BAK results in distinct activation kinetics of the cGAS/STING pathway with implications for mtDNA-mediated paracrine inflammatory signaling.

Keywords:  AFM; BAK; BAX; BCL-2; inflammatory cell death; membrane pore; mitochondria; pore-forming protein; single-molecule imaging; super-resolution microscopy

DOI:  https://doi.org/10.1016/j.molcel.2022.01.008
Platelets. 2022 Feb 03. 1-3

Platelet-derived respiratory-competent mitochondria transfer to mesenchymal stem cells to promote wound healing via metabolic reprogramming.

Enlin Chen, Zhe Chen, Linxi Chen, Xiaoling Hu.

  Mitochondria regulate intracellular metabolism and are also involved in intercellular transfer in vitro and in vivo, thereby affecting the function of adjacent cells. Mitochondria can also be transferred to various differentiated cells to improve their respiratory function, ATP production, as well as protect damaged cells from apoptosis. Both in vivo and in vitro, mitochondria can be transferred from one cell to another to regulate cellular metabolism under physiological or pathophysiological conditions, referred to as "mitochondrial translocation". Mitochondrial translocation is associated in various situations such as repairing damaged cells, promoting cancer progression and enhancing chemoresistance. Platelets contain mitochondria that promote energy metabolism and various growth factors, thus playing an important role in pathophysiological processes such as thrombosis, hemostasis, inflammation and wound healing. Current studies suggest that mesenchymal stem cells (MSCs) can communicate with their microenvironment through bidirectional alternation of mitochondria to improve their wound healing capacity. Platelets or platelet-containing preparations such as platelet-rich plasma (PRP) can stimulate the proliferation and pro-angiogenic properties of MSCs under oxidative stress to enhance their survival. Recent studies by Levoux et al. have shown that activated platelet-derived mitochondria have the respiratory capacity to translocate to MSCs and stimulate the pro-angiogenic properties of MSCs through metabolic reprogramming, thereby promoting angiogenesis and wound healing. The mechanism of mitochondrial internalization of cells and energy metabolism is a new example of mitochondrial translocation altering somatic cell behavior and viability. Therefore, we aim to comment the mechanisms of platelet mitochondrial translocation and metabolic reprogramming of MSCs, suggesting that platelets or platelet-containing preparations such as platelet-rich plasma (PRP) may provide a practical guide for tissue injury treatment.

Keywords:  Mitochondria; stem cells; wound healing

DOI:  https://doi.org/10.1080/09537104.2021.1961717
Redox Biol. 2022 Jan 29. pii: S2213-2317(22)00024-6. [Epub ahead of print]50 102252

Flow-induced endothelial mitochondrial remodeling mitigates mitochondrial reactive oxygen species production and promotes mitochondrial DNA integrity in a p53-dependent manner.

Junchul Shin, Soon-Gook Hong, Soo Young Choi, Meghan E Rath, Jason Saredy, Daniel G Jovin, Jacqueline Sayoc, Hye-Sang Park, Satoru Eguchi, Victor Rizzo, Rosario Scalia, Hong Wang, Steven R Houser, Joon-Young Park.

  Tumor suppressor p53 plays a pivotal role in orchestrating mitochondrial remodeling by regulating their content, fusion/fission processes, and intracellular signaling molecules that are associated with mitophagy and apoptosis pathways. In order to determine a molecular mechanism underlying flow-mediated mitochondrial remodeling in endothelial cells, we examined, herein, the role of p53 on mitochondrial adaptations to physiological flow and its relevance to vascular function using endothelial cell-specific p53 deficient mice. We observed no changes in aerobic capacity, basal blood pressure, or endothelial mitochondrial phenotypes in the endothelial p53 mull animals. However, after 7 weeks of voluntary wheel running exercise, blood pressure reduction and endothelial mitochondrial remodeling (biogenesis, elongation, and mtDNA replication) were substantially blunted in endothelial p53 null animals compared to the wild-type, subjected to angiotensin II-induced hypertension. In addition, endothelial mtDNA lesions were significantly reduced following voluntary running exercise in wild-type mice, but not in the endothelial p53 null mice. Moreover, in vitro studies demonstrated that unidirectional laminar flow exposure significantly increased key putative regulators for mitochondrial remodeling and reduced mitochondrial reactive oxygen species generation and mtDNA damage in a p53-dependent manner. Mechanistically, unidirectional laminar flow instigated translocalization of p53 into the mitochondrial matrix where it binds to mitochondrial transcription factor A, TFAM, resulting in improving mtDNA integrity. Taken together, our findings suggest that p53 plays an integral role in mitochondrial remodeling under physiological flow condition and the flow-induced p53-TFAM axis may be a novel molecular intersection for enhancing mitochondrial homeostasis in endothelial cells.

Keywords:  Endothelial cell; Fluid shear stress; Mitochondria; TFAM; mtROS; p53

DOI:  https://doi.org/10.1016/j.redox.2022.102252
Nat Commun. 2022 Feb 03. 13(1): 653

TAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A.

Jun-Ha Hwang, Kyung Min Kim, Ho Taek Oh, Gi Don Yoo, Mi Gyeong Jeong, Hyun Lee, Joori Park, Kwon Jeong, Yoon Ki Kim, Young-Gyu Ko, Eun Sook Hwang, Jeong-Ho Hong.

Mitochondria are energy-generating organelles and mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular stimuli, including exercise. However, the mechanisms underlying mitochondrial biogenesis remain unknown. Here, we demonstrate that transcriptional coactivator with PDZ-binding motif (TAZ) stimulates mitochondrial biogenesis in skeletal muscle. In muscle-specific TAZ-knockout (mKO) mice, mitochondrial biogenesis, respiratory metabolism, and exercise ability were decreased compared to wild-type mice. Mechanistically, TAZ stimulates the translation of mitochondrial transcription factor A via Ras homolog enriched in brain (Rheb)/Rheb like 1 (Rhebl1)-mTOR axis. TAZ stimulates Rhebl1 expression via TEA domain family transcription factor. Rhebl1 introduction by adeno-associated virus or mTOR activation recovered mitochondrial biogenesis in mKO muscle. Physiologically, mKO mice did not stimulate exercise-induced mitochondrial biogenesis. Collectively, our results suggested that TAZ is a novel stimulator for mitochondrial biogenesis and exercise-induced muscle adaptation.

DOI: https://doi.org/10.1038/s41467-022-28247-2
Nat Commun. 2022 Feb 03. 13(1): 651

Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.

Eirini Lionaki, Ilias Gkikas, Ioanna Daskalaki, Maria-Konstantina Ioannidi, Maria I Klapa, Nektarios Tavernarakis.

Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.

DOI: https://doi.org/10.1038/s41467-022-28272-1