bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2022‒01‒30
twelve papers selected by
Edmond Chan
Queen’s University, School of Medicine

  1. Dev Cell. 2022 Jan 24. pii: S1534-5807(21)01040-6. [Epub ahead of print]57(2): 260-276.e9
      Metabolic flexibility is a hallmark of many cancers where mitochondrial respiration is critically involved, but the molecular underpinning of mitochondrial control of cancer metabolic reprogramming is poorly understood. Here, we show that reverse electron transfer (RET) through respiratory chain complex I (RC-I) is particularly active in brain cancer stem cells (CSCs). Although RET generates ROS, NAD+/NADH ratio turns out to be key in mediating RET effect on CSC proliferation, in part through the NAD+-dependent Sirtuin. Mechanistically, Notch acts in an unconventional manner to regulate RET by interacting with specific RC-I proteins containing electron-transporting Fe-S clusters and NAD(H)-binding sites. Genetic and pharmacological interference of Notch-mediated RET inhibited CSC growth in Drosophila brain tumor and mouse glioblastoma multiforme (GBM) models. Our results identify Notch as a regulator of RET and RET-induced NAD+/NADH balance, a critical mechanism of metabolic reprogramming and a metabolic vulnerability of cancer that may be exploited for therapeutic purposes.
    Keywords:  NAD(+)/NADH; Sirtuin; Warburg effect; glioblastoma multiforme; inflammation; metabolic reprogramming; mitochondrial complex I; non-canonical Notch signaling; reactive oxygen species; reverse electron transport
  2. Cell Rep. 2022 Jan 25. pii: S2211-1247(21)01805-2. [Epub ahead of print]38(4): 110290
      Invaginations of the mitochondrial inner membrane, termed cristae, are hubs for oxidative phosphorylation. The mitochondrial contact site and cristae organizing system (MICOS) and the dimeric F1Fo-ATP synthase play important roles in controlling cristae architecture. A fraction of the MICOS core subunit Mic10 is found in association with the ATP synthase, yet it is unknown whether this interaction is of relevance for mitochondrial or cellular functions. Here, we established conditions to selectively study the role of Mic10 at the ATP synthase. Mic10 variants impaired in MICOS functions stimulate ATP synthase oligomerization like wild-type Mic10 and promote efficient inner membrane energization, adaptation to non-fermentable carbon sources, and respiratory growth. Mic10's functions in respiratory growth largely depend on Mic10ATPsynthase, not on Mic10MICOS. We conclude that Mic10 plays a dual role as core subunit of MICOS and as partner of the F1Fo-ATP synthase, serving distinct functions in cristae shaping and respiratory adaptation and growth.
    Keywords:  ATP synthase; MICOS; Mic10; cristae organization; inner membrane; membrane architecture; membrane potential; metabolic adaptation; mitochondria; respiration
  3. iScience. 2022 Jan 21. 25(1): 103715
      Mitochondrial dysfunction causes muscle wasting in many diseases and probably also during aging. The underlying mechanism is poorly understood. We generated transgenic mice with unbalanced mitochondrial protein loading and import, by moderately overexpressing the nuclear-encoded adenine nucleotide translocase, Ant1. We found that these mice progressively lose skeletal muscle. Ant1-overloading reduces mitochondrial respiration. Interestingly, it also induces small heat shock proteins and aggresome-like structures in the cytosol, suggesting increased proteostatic burden due to accumulation of unimported mitochondrial preproteins. The transcriptome of Ant1-transgenic muscles is drastically remodeled to counteract proteostatic stress, by repressing protein synthesis and promoting proteasomal function, autophagy, and lysosomal amplification. These proteostatic adaptations collectively reduce protein content thereby reducing myofiber size and muscle mass. Thus, muscle wasting can occur as a trade-off of adaptation to mitochondria-induced proteostatic stress. This finding could have implications for understanding the mechanism of muscle wasting, especially in diseases associated with Ant1 overexpression, including facioscapulohumeral dystrophy.
    Keywords:  Biological sciences; Cell biology; Cellular physiology; Functional aspects of cell biology
  4. Mol Biol Cell. 2022 Jan 26. mbcE21030143
      Assembly of the dimeric complex III (CIII2) in the mitochondrial inner membrane is an intricate process, in which several accessory proteins are involved as assembly factors. Despite numerous studies, this process is yet to be fully understood. Here we report the identification of human OCIAD2 (Ovarian Carcinoma Immunoreactive Antigen domain containing protein 2) protein as an assembly factor for CIII2. OCIAD2 was found deregulated in several carcinomas and also in some neurogenerative disorders, however its non-pathological role had not been elucidated.  We have shown that OCIAD2 localizes to mitochondria and interacts with electron transport chain (ETC) proteins. Complete loss of OCIAD2 using gene editing in HEK293 cells resulted in abnormal mitochondrial morphology, a substantial decrease of both CIII2 and supercomplex III2+IV, and reduction in CIII enzymatic activity. Identification of OCIAD2 as a protein required for assembly of functional CIII2 provides a new insight into the biogenesis and architecture of the ETC. Elucidating the mechanism of OCIAD2 action is important both for the understanding of cellular metabolism and for an understanding of its role in malignant transformation.
  5. J Lipid Res. 2022 Jan 20. pii: S0022-2275(22)00005-0. [Epub ahead of print] 100172
      Disturbances in lipid homeostasis can cause mitochondrial dysfunction and lipotoxicity. Perilipin 5 (PLIN5) decorates intracellular lipid droplets (LD) in oxidative tissues and controls triacylglycerol (TG) turnover via its interactions with Adipose triglyceride lipase (ATGL) and the ATGL co-activator Comparative gene identification-58 (CGI-58). Furthermore, PLIN5 anchors mitochondria to the LD membrane via the outermost part of the carboxyl-terminus. However, the role of this LD-mitochondria coupling (LDMC) in cellular energy catabolism is less established. In this study, we investigated the impact of PLIN5-mediated LDMC in comparison to disrupted LDMC on cellular TG homeostasis, FA oxidation, mitochondrial respiration and protein interaction. To do so, we established PLIN5 mutants deficient in LDMC whilst maintaining normal interactions with key lipolytic players. Radiotracer studies with cell lines stably overexpressing wild type or truncated PLIN5 revealed that LDMC has no significant impact on FA esterification upon lipid loading or TG catabolism during stimulated lipolysis. Moreover, we demonstrated that LDMC exerts a minor if any role in mitochondrial FA oxidation. In contrast, LDMC significantly improved the mitochondrial respiratory capacity and metabolic flexibility of lipid-challenged cardiomyocytes, which was corroborated by LDMC-dependent interactions of PLIN5 with mitochondrial proteins involved in mitochondrial respiration, dynamics and cristae organization. Taken together, this study suggests that PLIN5 preserves mitochondrial function by adjusting FA supply via the regulation of TG hydrolysis and that LDMC is a vital part of mitochondrial integrity.
    Keywords:  Adipose-triglyceride lipase; Comparative gene identification-58; Lipid droplets; PLIN5; cardiovascular disease; fatty acid oxidation; lipid droplet-mitochondria coupling; lipolysis; lipotoxicity; mitochondrial respiration
  6. mBio. 2022 Jan 25. e0209621
      Mitochondria are dynamic organelles vital for energy production with now appreciated roles in immune defense. During microbial infection, mitochondria serve as signaling hubs to induce immune responses to counteract invading pathogens like viruses. Mitochondrial functions are central to a variety of antiviral responses including apoptosis and type I interferon signaling (IFN-I). While apoptosis and IFN-I mediated by mitochondrial antiviral signaling (MAVS) are well-established defenses, new dimensions of mitochondrial biology are emerging as battlefronts during viral infection. Increasingly, it has become apparent that mitochondria serve as reservoirs for distinct cues that trigger immune responses and that alterations in mitochondrial morphology may also tip infection outcomes. Furthermore, new data are foreshadowing pivotal roles for classic, homeostatic facets of this organelle as host-virus interfaces, namely, the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) complexes like respiratory supercomplexes. Underscoring the importance of "housekeeping" mitochondrial activities in viral infection is the growing list of viral-encoded inhibitors including mimics derived from cellular genes that antagonize these functions. For example, virologs for ETC factors and several enzymes from the TCA cycle have been recently identified in DNA virus genomes and serve to pinpoint new vulnerabilities during infection. Here, we highlight recent advances for known antiviral functions associated with mitochondria as well as where the next battlegrounds may be based on viral effectors. Collectively, new methodology and mechanistic insights over the coming years will strengthen our understanding of how an ancient molecular truce continues to defend cells against viruses.
    Keywords:  C15orf48; DAMP; MAVS; MISTR; NDUFA4; OXPHOS; TCA cycle; apoptosis; interferon; micropeptides; mimics; mitochondria; mitochondrial dynamics; mtDNA; mtROS; mtdsRNA; pyroptosis; supercomplexes; virologs; virus
  7. FEBS Lett. 2022 Jan 28.
      Mitochondria are associated with various cellular activities critical to homeostasis, particularly in the nervous system. The plastic architecture of the mitochondrial network and its dynamic structure play crucial roles in ensuring that varying energetic demands are rapidly met to maintain neuronal and axonal energy homeostasis. Recent evidence associates ageing and neurodegeneration with anomalous neuronal metabolism, as age-dependent alterations of neuronal metabolism are now believed to occur prior to neurodegeneration. The brain has a high energy demand, which makes it particularly sensitive to mitochondrial dysfunction. Distinct cellular events causing oxidative stress or disruption of metabolism and mitochondrial homeostasis can trigger a neuropathology. This review explores the bioenergetic hypothesis for the neurodegenerative pathomechanisms, discussing factors leading to age-related brain hypometabolism and its contribution to cognitive decline. Recent research on the mitochondrial network in healthy nervous system cells, its response to stress and how it is affected by pathology, as well as current contributions to novel therapeutic approaches will be highlighted.
    Keywords:  Alzheimer; Huntington; Parkinson; ROS; ageing; axon; mitochondria; mitophagy; neurodegeneration; neuron
  8. Antioxid Redox Signal. 2022 Jan 24.
      SIGNIFICANCE: Mitochondria produce most of the cellular ATP through the process of oxidative phosphorylation. Energy metabolism in the mitochondria is associated with the production of reactive oxygen species (ROS). Excessive ROS production leads to oxidative stress and compromises cellular physiology. Energy metabolism in the mitochondria depends on nutrient flux and cellular metabolic needs, which are in turn connected with the feeding/fasting cycle. In animals, the feeding/fasting cycle is controlled by the circadian clock that generates 24-hour rhythms in behavior, metabolism and signaling. Recent Advances. Here, we discuss the role of the circadian clock and rhythms in mitochondria on ROS homeostasis. Circadian clock is involved in mitochondrial ROS production and detoxification through control of nutrient flux and oxidation, uncoupling, antioxidant defense and mitochondrial dynamics.CRITICAL ISSUES: Little is known on molecular mechanisms of circadian control of mitochondria functions. The circadian clock regulates the expression and activity of mitochondrial metabolic and antioxidant enzymes. The regulation involves a direct transcriptional control by CLOCK/BMAL1, NRF2 transcriptional network and sirtuin dependent posttranslational protein modifications. Future Perspectives. We hypothesize that the circadian clock orchestrates mitochondria physiology to synchronize it with the feeding/fasting cycle. Circadian coordination of mitochondrial function couples energy metabolism with diets and contributes to antioxidant defense to prevent metabolic diseases and delay aging.
  9. J Biochem. 2022 Jan 26. pii: mvac005. [Epub ahead of print]
      In addition to the cytoplasmic translation system, eukaryotic cells house additional protein synthesis machinery in mitochondria. The importance of this in organello translation is exemplified by clinical pathologies associated with mutations in mitochondrial translation factors. Although a detailed understanding of mitochondrial translation has long been awaited, quantitative, comprehensive, and spatiotemporal measurements have posed analytic challenges. The recent development of novel approaches for studying mitochondrial protein synthesis has overcome these issues and expands our understanding of the unique translation system. Here, we review the current technologies for the investigation of mitochondrial translation and the insights provided by their application.
    Keywords:  FUNCAT; Mitochondria; Mitoribosome; Ribosome profiling; Translation
  10. Antioxid Redox Signal. 2022 Jan 24.
      BACKGROUND: Mitochondrial Na+ has been discovered as a new second messenger regulating inner mitochondrial membrane (IMM) fluidity and ROS production by complex III (CIII). However, the roles of mitochondrial Na+ in mitochondrial redox signalling go beyond than initially expected.SIGNIFICANCE: In this review, we systematize the current knowledge on mitochondrial Na+ homeostasis and its implications on different modes of ROS production by mitochondria. Na+ behaves as a positive modulator of forward mitochondrial ROS production by either complex III (CIII) or by decreasing antioxidant capacity of mitochondria, and as a potential negative modulator of reverse electron transfer (RET) by complex I (CI). Such duality depends on the bioenergetic status, cation and redox contexts, and can either lead to potential adaptations or cell death.
    FUTURE DIRECTIONS: Direct Na+ interaction with phospholipids, proven in the IMM, allows us to hypothesize its potential role in the existence and function of lipid rafts in other biological membranes regarding redox homeostasis, as well as the potential role of other monovalent cations in membrane biology. Thus, we provide the reader an update on the emerging field of mitochondrial Na+ homeostasis and its relationship with mitochondrial redox signalling.
  11. J Vis Exp. 2022 Jan 07.
      Mitochondria are key metabolic and regulatory organelles that determine the energy supply as well as the overall health of the cell. In skeletal muscle, mitochondria exist in a series of complex morphologies, ranging from small oval organelles to a broad, reticulum-like network. Understanding how the mitochondrial reticulum expands and develops in response to diverse stimuli such as alterations in energy demand has long been a topic of research. A key aspect of this growth, or biogenesis, is the import of precursor proteins, originally encoded by the nuclear genome, synthesized in the cytosol, and translocated into various mitochondrial sub-compartments. Mitochondria have developed a sophisticated mechanism for this import process, involving many selective inner and outer membrane channels, known as the protein import machinery (PIM). Import into the mitochondrion is dependent on viable membrane potential and the availability of organelle-derived ATP through oxidative phosphorylation. Therefore its measurement can serve as a measure of organelle health. The PIM also exhibits a high level of adaptive plasticity in skeletal muscle that is tightly coupled to the energy status of the cell. For example, exercise training has been shown to increase import capacity, while muscle disuse reduces it, coincident with changes in markers of mitochondrial content. Although protein import is a critical step in the biogenesis and expansion of mitochondria, the process is not widely studied in skeletal muscle. Thus, this paper outlines how to use isolated and fully functional mitochondria from skeletal muscle to measure protein import capacity in order to promote a greater understanding of the methods involved and an appreciation of the importance of the pathway for organelle turnover in exercise, health, and disease.
  12. Front Microbiol. 2021 ;12 780768
      Mitochondria, which is essential for adequate innate immune response, energy metabolism and mitochondria reactive oxygen species (ROS) production, might be in the cross fire of Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host cell defense. However, little is known about interactions between mitochondria and SARS-CoV-2. We performed fluorescent microscopy and found an enrichment of SARS-CoV-2 replication products double stranded RNA (dsRNA) within mitochondria. The entry process of dsRNA might be mediated by Tom20 as observed by reduced mitochondrial localization of SARS-CoV-2 dsRNA in Tom20 knockdown cells. Importantly, decreased mitochondrial localization of dsRNA, as well as mitochondrial membrane stabilizers mdivi-1 and cyclosporin A, inhibited viral load in cells. Next, we detected mitochondrial dysfunction caused by SARS-CoV-2 infection, including mitochondrial membrane depolarization, mitochondrial permeability transition pore opening and increased ROS release. In response to mitochondrial damage, we observed an increase in expression and mitochondrial accumulation of Pink1 and Parkin proteins, as well as Pink-1-mediated recruitment of P62 to mitochondria, suggesting initiated mitophagy for mitochondrial quality control and virus clearance. Nevertheless, we observed that mitophagy was inhibited and stayed in early stage with an unchanged Hsp60 expression post SARS-CoV-2 infection. This might be one of the anti-autophagy strategies of SARS-CoV-2 and we used co-immunoprecipitation to found that SARS-CoV-2 infection inhibited P62 and LC3 binding which plays a critical role in selective envelopment of substrates into autophagosomes. Our results suggest that mitochondria are closely involved in SARS-CoV-2 replication and mitochondrial homeostasis is disrupted by SARS-CoV-2 in the virus-cell confrontation.
    Keywords:  SARS-CoV-2; Tom20; mitochondria; mitophagy; viral RNA localization