bims-mikwok 2021-07-25 papers

Mol Neurobiol. 2021 Jul 18.

Mitochondrial Quality Control in Cerebral Ischemia-Reperfusion Injury.

Ischemic stroke is one of the leading causes of death and also a major cause of adult disability worldwide. Revascularization via reperfusion therapy is currently a standard clinical procedure for patients with ischemic stroke. Although the restoration of blood flow (reperfusion) is critical for the salvage of ischemic tissue, reperfusion can also, paradoxically, exacerbate neuronal damage through a series of cellular alterations. Among the various theories postulated for ischemia/reperfusion (I/R) injury, including the burst generation of reactive oxygen species (ROS), activation of autophagy, and release of apoptotic factors, mitochondrial dysfunction has been proposed to play an essential role in mediating these pathophysiological processes. Therefore, strict regulation of the quality and quantity of mitochondria via mitochondrial quality control is of great importance to avoid the pathological effects of impaired mitochondria on neurons. Furthermore, timely elimination of dysfunctional mitochondria via mitophagy is also crucial to maintain a healthy mitochondrial network, whereas intensive or excessive mitophagy could exacerbate cerebral I/R injury. This review will provide a comprehensive overview of the effect of mitochondrial quality control on cerebral I/R injury and introduce recent advances in the understanding of the possible signaling pathways of mitophagy and potential factors responsible for the double-edged roles of mitophagy in the pathological processes of cerebral I/R injury.

Keywords: Cerebral ischemia; Mitochondrial; Mitochondrial quality control; Mitophagy; Reperfusion

DOI: https://doi.org/10.1007/s12035-021-02494-8

Autophagy. 2021 Jul 18. 1-3

SAMM50 is a receptor for basal piecemeal mitophagy and acts with SQSTM1/p62 in OXPHOS-induced mitophagy.

Yakubu Princely Abudu, Stephane Mouilleron, Sharon A Tooze, Trond Lamark, Terje Johansen.

Mitophagy, the clearance of surplus or damaged mitochondria or mitochondrial parts by autophagy, is important for maintenance of cellular homeostasis. Whereas knowledge on programmed and stress-induced mitophagy is increasing, much less is known about mechanisms of basal mitophagy. Recently, we identified SAMM50 (SAMM50 sorting and assembly machinery component) as a receptor for piecemeal degradation of components of the sorting and assembly machinery (SAM) complex and mitochondrial contact site and cristae organizing system (MICOS) complexes. SAMM50 interacts directly with Atg8-family proteins through a canonical LIR motif and with SQSTM1/p62 to mediate basal piecemeal mitophagy. During a metabolic switch to oxidative phosphorylation (OXPHOS), SAMM50 cooperates with SQSTM1 to mediate efficient piecemeal mitophagy.

Keywords: Atg8; MICOS; OXPHOS; SAMM50; SQSTM1; basal; metabolic switch; p62; piecemeal mitophagy

DOI: https://doi.org/10.1080/15548627.2021.1953846

Biophys J. 2021 Jul 20. pii: S0006-3495(21)00598-1. [Epub ahead of print]

MitoWave: Spatio-temporal analysis of mitochondrial membrane potential fluctuations during ischemia-reperfusion.

Deepthi Ashok, Brian O'Rourke.

Mitochondria exhibit unstable inner membrane potentials (ΔΨm) when subjected to stress, such as during Ischemia/Reperfusion (I/R). Understanding the mechanism of ΔΨm instability involves characterizing and quantifying this phenomenon in an unbiased and reproducible manner. Here, we describe a simple analytical workflow called 'MitoWave' that combines wavelet transform methods and image segmentation to unravel dynamic ΔΨm changes in the cardiac mitochondrial network during I/R. In vitro ischemia was effected by placing a glass coverslip on a monolayer of neonatal mouse ventricular myocytes (NMVMs) for 1 hour and removing the coverslip to allowed for reperfusion, revealing complex oscillatory ΔΨm. MitoWave analysis was then used to identify individual mitochondrial clusters within the cells and track their intrinsic oscillation frequencies over the course of reperfusion. Responses segregated into five typical behaviors quantified by MitoWave that were corroborated by visual inspection of the time series. Statistical analysis of the distribution of oscillating mitochondrial clusters during reperfusion showed significant differences between the five different outcomes. Features such as the time-point of ΔΨm depolarization during I/R, area of mitochondrial clusters, and time-resolved frequency components dAuring reperfusion were determined per cell and per mitochondrial cluster. Mitochondria from NMVMs subjected to I/R oscillate in the frequency range of 8.6-45mHz, with a mean of 8.73±4.35mHz. Oscillating clusters had smaller areas ranging from 49.8±1.2 μm2 while non-oscillating clusters had larger areas 66±1.5μm2. A negative correlation between frequency and mitochondrial cluster area was observed. We also observed that late ΔΨm loss during ischemia correlated with early ΔΨm stabilization after oscillation on reperfusion. Thus, MitoWave analysis provides a semi-automated method to quantify complex time-resolved mitochondrial behavior in an easy to follow workflow, enabling unbiased, reproducible quantitation of complex non-stationary cellular phenomena.

Keywords: image processing; ischemia; mitochondrial membrane potential; oscillation; oxidative phosphorylation; reperfusion; time-series analysis; wavelet

DOI: https://doi.org/10.1016/j.bpj.2021.05.033

EMBO Rep. 2021 Jul 23. e51954

Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development.

Sergi Casellas-Díaz, Raquel Larramona-Arcas, Guillem Riqué-Pujol, Paula Tena-Morraja, Claudia Müller-Sánchez, Marc Segarra-Mondejar, Aleix Gavaldà-Navarro, Francesc Villarroya, Manuel Reina, Ofelia M Martínez-Estrada, Francesc X Soriano.

Mfn2 is a mitochondrial fusion protein with bioenergetic functions implicated in the pathophysiology of neuronal and metabolic disorders. Understanding the bioenergetic mechanism of Mfn2 may aid in designing therapeutic approaches for these disorders. Here we show using endoplasmic reticulum (ER) or mitochondria-targeted Mfn2 that Mfn2 stimulation of the mitochondrial metabolism requires its localization in the ER, which is independent of its fusion function. ER-located Mfn2 interacts with mitochondrial Mfn1/2 to tether the ER and mitochondria together, allowing Ca2+ transfer from the ER to mitochondria to enhance mitochondrial bioenergetics. The physiological relevance of these findings is shown during neurite outgrowth, when there is an increase in Mfn2-dependent ER-mitochondria contact that is necessary for correct neuronal arbor growth. Reduced neuritic growth in Mfn2 KO neurons is recovered by the expression of ER-targeted Mfn2 or an artificial ER-mitochondria tether, indicating that manipulation of ER-mitochondria contacts could be used to treat pathologic conditions involving Mfn2.

Keywords: Ca2+; ER-mitochondria tethering; Mfn2; neuritic growth

DOI: https://doi.org/10.15252/embr.202051954

Oxid Med Cell Longev. 2021 ;2021 6670579

The Role of Mitochondria in Liver Ischemia-Reperfusion Injury: From Aspects of Mitochondrial Oxidative Stress, Mitochondrial Fission, Mitochondrial Membrane Permeable Transport Pore Formation, Mitophagy, and Mitochondria-Related Protective Measures.

Haifeng Zhang, Qi Yan, Xuan Wang, Xin Chen, Ying Chen, Jian Du, Lijian Chen.

Ischemia-reperfusion injury (IRI) has indeed been shown as a main complication of hepatectomy, liver transplantation, trauma, and hypovolemic shock. A large number of studies have confirmed that microvascular and parenchymal damage is mainly caused by reactive oxygen species (ROS), which is considered to be a major risk factor for IRI. Under normal conditions, ROS as a kind of by-product of cellular metabolism can be controlled at normal levels. However, when IRI occurs, mitochondrial oxidative phosphorylation is inhibited. In addition, oxidative respiratory chain damage leads to massive consumption of adenosine triphosphate (ATP) and large amounts of ROS. Additionally, mitochondrial dysfunction is involved in various organs and tissues in IRI. On the one hand, excessive free radicals induce mitochondrial damage, for instance, mitochondrial structure, number, function, and energy metabolism. On the other hand, the disorder of mitochondrial fusion and fission results in further reduction of the number of mitochondria so that it is not enough to clear excessive ROS, and mitochondrial structure changes to form mitochondrial membrane permeable transport pores (mPTPs), which leads to cell necrosis and apoptosis, organ failure, and metabolic dysfunction, increasing morbidity and mortality. According to the formation mechanism of IRI, various substances have been discovered or synthesized for specific targets and cell signaling pathways to inhibit or slow the damage of liver IRI to the body. Here, based on the development of this field, this review describes the role of mitochondria in liver IRI, from aspects of mitochondrial oxidative stress, mitochondrial fusion and fission, mPTP formation, and corresponding protective measures. Therefore, it may provide references for future clinical treatment and research.

DOI: https://doi.org/10.1155/2021/6670579

Commun Biol. 2021 Jul 21. 4(1): 894

Lixiang Wang, Xin Li, Yuki Hanada, Nao Hasuzawa, Yoshinori Moriyama, Masatoshi Nomura, Ken Yamamoto.

Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

DOI: https://doi.org/10.1038/s42003-021-02413-6