bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023‒06‒11
twelve papers selected by
Avinash N. Mukkala
University of Toronto
  1. ATF4 regulates mitochondrial content, morphology, and function in differentiating skeletal muscle myotubes.
  2. A cytosolic surveillance mechanism activates the mitochondrial UPR.
  3. Eating your mitochondria-when too much of a good thing turns bad.
  4. The multiple links between actin and mitochondria.
  5. Defective mitochondrial import as a challenge for cellular protein homeostasis.
  6. A molecular rotor FLIM probe reveals dynamic coupling between mitochondrial inner membrane fluidity and cellular respiration.
  7. MICU1 deficiency alters mitochondrial morphology and cytochrome C release.
  8. Delivery of low-density lipoprotein from endocytic carriers to mitochondria supports steroidogenesis.
  9. Severe burn-induced mitochondrial recruitment of calpain causes aberrant mitochondrial dynamics and heart dysfunction.
  10. Calcium and bicarbonate signaling pathways have pivotal, resonating roles in matching ATP production to demand.
  11. Megamitochondria plasticity: function transition from adaption to disease.
  12. Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging.
  1. Am J Physiol Cell Physiol. 2023 Jun 05.
    ATF4 regulates mitochondrial content, morphology, and function in differentiating skeletal muscle myotubes.
    Jonathan M Memme, Victoria C Sanfrancesco, David A Hood.
      Mitochondrial function is widely recognized as a major determinant of health, emphasizing the importance of understanding the mechanisms promoting mitochondrial quality in various tissues. Recently, the mitochondrial unfolded protein response (UPRmt) has come into focus as a modulator of mitochondrial homeostasis, particularly in stress conditions. In muscle, the necessity for ATF4 and its role in regulating mitochondrial quality control (MQC) has yet to be determined. We overexpressed (OE) and knocked down ATF4 in C2C12 myoblasts, differentiated them to myotubes for 5 days, and subjected them to acute (ACA) or chronic (CCA) contractile activity. ATF4 mediated myotube formation through the regulated expression of myogenic factors, mainly Myc and MyoD, and supressed mitochondrial biogenesis basally through PGC-1a. However, our data also show that ATF4 expression levels are directly related to mitochondrial fusion and dynamics, UPRmt activation, as well as lysosomal biogenesis and autophagy. Thus, ATF4 promoted enhanced mitochondrial networking, protein handling, and capacity for clearance of dysfunctional organelles under stress conditions, despite lower levels of mitophagy flux with OE. Indeed, we found that ATF4 promoted the formation of a smaller pool of high functioning mitochondria that are more responsive to contractile activity, have higher oxygen consumption rates and lower reactive oxygen species levels. These data provide evidence that ATF4 is both necessary and sufficient for mitochondrial quality control and adaptation during both differentiation and contractile activity, thus advancing the current understanding of ATF4 beyond its canonical functions, to include the regulation of mitochondrial morphology, lysosomal biogenesis and mitophagy in muscle cells.
    Keywords:  ATF4; mitochondrial quality control; mitochondrial unfolded protein response; mitophagy and lysosomal biogenesis; skeletal muscle C2C12
    DOI:  https://doi.org/10.1152/ajpcell.00080.2023
  2. Nature. 2023 Jun 07.
    A cytosolic surveillance mechanism activates the mitochondrial UPR.
    F X Reymond Sutandy, Ines Gößner, Georg Tascher, Christian Münch.
      The mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis1,2. Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPRmt (refs. 3,4). Here, we show that UPRmt signalling is driven by the release of two individual signals in the cytosol-mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPRmt; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPRmt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPRmt. These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling in human cells.
    DOI:  https://doi.org/10.1038/s41586-023-06142-0
  3. EMBO J. 2023 Jun 05. e114542
    Eating your mitochondria-when too much of a good thing turns bad.
    Léa P Wilhelm, Ian G Ganley.
      How mitophagy is turned on to remove damaged or excess mitochondria from cells has been well-studied, but less is known about how the pathway is turned off to avoid "over-eating" of mitochondria under basal conditions. Three new studies now reveal the disease-associated FBXL4 protein as an important negative regulator of constitutive mitophagy, controlling the stability of mitophagy receptors BNIP3 and NIX.
    DOI:  https://doi.org/10.15252/embj.2023114542
  4. Nat Rev Mol Cell Biol. 2023 Jun 05.
    The multiple links between actin and mitochondria.
    Tak Shun Fung, Rajarshi Chakrabarti, Henry N Higgs.
      Actin plays many well-known roles in cells, and understanding any specific role is often confounded by the overlap of multiple actin-based structures in space and time. Here, we review our rapidly expanding understanding of actin in mitochondrial biology, where actin plays multiple distinct roles, exemplifying the versatility of actin and its functions in cell biology. One well-studied role of actin in mitochondrial biology is its role in mitochondrial fission, where actin polymerization from the endoplasmic reticulum through the formin INF2 has been shown to stimulate two distinct steps. However, roles for actin during other types of mitochondrial fission, dependent on the Arp2/3 complex, have also been described. In addition, actin performs functions independent of mitochondrial fission. During mitochondrial dysfunction, two distinct phases of Arp2/3 complex-mediated actin polymerization can be triggered. First, within 5 min of dysfunction, rapid actin assembly around mitochondria serves to suppress mitochondrial shape changes and to stimulate glycolysis. At a later time point, at more than 1 h post-dysfunction, a second round of actin polymerization prepares mitochondria for mitophagy. Finally, actin can both stimulate and inhibit mitochondrial motility depending on the context. These motility effects can either be through the polymerization of actin itself or through myosin-based processes, with myosin 19 being an important mitochondrially attached myosin. Overall, distinct actin structures assemble in response to diverse stimuli to affect specific changes to mitochondria.
    DOI:  https://doi.org/10.1038/s41580-023-00613-y
  5. FEBS Lett. 2023 Jun 05.
    Defective mitochondrial import as a challenge for cellular protein homeostasis.
    Klaudia K Maruszczak, Selvaraj Ayyamperumal, Agnieszka Chacinska.
      Mitochondria are organelles indispensable for the correct functioning of eukaryotic cells. Their significance for cellular homeostasis is manifested by the existence of complex quality control pathways that monitor organellar fitness. Mitochondrial biogenesis relies on the efficient import of mitochondrial precursor proteins, a large majority of which are encoded by nuclear DNA and synthesized in the cytosol. This creates a demand for highly specialized import routes that comprise cytosolic factors and organellar translocases. The passage of newly encoded mitochondrial precursor proteins through the cytosol to the translocase of the outer mitochondrial membrane (TOM) is under tight surveillance. As a result of mitochondrial import defects, mitochondrial precursor proteins accumulate in the cytosol or clog the TOM complex, which in turn stimulates cellular stress responses to minimize the consequences of these challenges. These responses are critical for maintaining protein homeostasis under conditions of mitochondrial stress. The present review summarizes recent advances in the field of mitochondrial protein import quality control and discusses the role of this quality control within the network of cellular mechanisms that maintain the cellular homeostasis of proteins.
    Keywords:  cellular stress responses; mitochondria; mitochondrial dysfunction; mitochondrial quality control; protein aggregates; protein homeostasis
    DOI:  https://doi.org/10.1002/1873-3468.14677
  6. Proc Natl Acad Sci U S A. 2023 Jun 13. 120(24): e2213241120
    A molecular rotor FLIM probe reveals dynamic coupling between mitochondrial inner membrane fluidity and cellular respiration.
    Gaurav Singh, Geen George, Sufi O Raja, Ponnuvel Kandaswamy, Manoj Kumar, Shashi Thutupalli, Sunil Laxman, Akash Gulyani.
      The inner mitochondrial membrane (IMM), housing components of the electron transport chain (ETC), is the site for respiration. The ETC relies on mobile carriers; therefore, it has long been argued that the fluidity of the densely packed IMM can potentially influence ETC flux and cell physiology. However, it is unclear if cells temporally modulate IMM fluidity upon metabolic or other stimulation. Using a photostable, red-shifted, cell-permeable molecular-rotor, Mitorotor-1, we present a multiplexed approach for quantitatively mapping IMM fluidity in living cells. This reveals IMM fluidity to be linked to cellular-respiration and responsive to stimuli. Multiple approaches combining in vitro experiments and live-cell fluorescence (FLIM) lifetime imaging microscopy (FLIM) show Mitorotor-1 to robustly report IMM 'microviscosity'/fluidity through changes in molecular free volume. Interestingly, external osmotic stimuli cause controlled swelling/compaction of mitochondria, thereby revealing a graded Mitorotor-1 response to IMM microviscosity. Lateral diffusion measurements of IMM correlate with microviscosity reported via Mitorotor-1 FLIM-lifetime, showing convergence of independent approaches for measuring IMM local-order. Mitorotor-1 FLIM reveals mitochondrial heterogeneity in IMM fluidity; between-and-within cells and across single mitochondrion. Multiplexed FLIM lifetime imaging of Mitorotor-1 and NADH autofluorescence reveals that IMM fluidity positively correlates with respiration, across individual cells. Remarkably, we find that stimulating respiration, through nutrient deprivation or chemically, also leads to increase in IMM fluidity. These data suggest that modulating IMM fluidity supports enhanced respiratory flux. Our study presents a robust method for measuring IMM fluidity and suggests a dynamic regulatory paradigm of modulating IMM local order on changing metabolic demand.
    Keywords:  fluidity; fluorescence lifetime; fluorescent probe; metabolism; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2213241120
  7. Cell Calcium. 2023 Jun 02. pii: S0143-4160(23)00077-5. [Epub ahead of print]113 102765
    MICU1 deficiency alters mitochondrial morphology and cytochrome C release.
    Benjamin Gottschalk, Roland Malli, Wolfgang F Graier.
      The mitochondrial inner boundary membrane harbors a protein called MICU1, which is sensitive to Ca2+ and binds to the MICOS components Mic60 and CHCHD2. Changes in the mitochondrial cristae junction structure and organization in MICU1-/- cells lead to increased cytochrome c release, membrane potential rearrangement, and changes in mitochondrial Ca2+ uptake dynamics. These findings shed new light on the multifaceted role of MICU1, highlighting its involvement not only as an interaction partner and regulator of the MCU complex but also as a crucial determinant of mitochondrial ultrastructure and, thus, an essential player in processes initiating apoptosis.
    Keywords:  Apoptosis; Ca(2+) signaling; Cristae junction; MICOS-complex; MICU1; Mitochondria
    DOI:  https://doi.org/10.1016/j.ceca.2023.102765
  8. Nat Cell Biol. 2023 Jun 05.
    Delivery of low-density lipoprotein from endocytic carriers to mitochondria supports steroidogenesis.
    Yu-Xia Zhou, Jian Wei, Gang Deng, Ao Hu, Pu-Yu Sun, Xiaolu Zhao, Bao-Liang Song, Jie Luo.
      The low-density lipoprotein (LDL) is a major cholesterol carrier in circulation and is internalized into cells through LDL receptor (LDLR)-mediated endocytosis. The LDLR protein is highly expressed in the steroidogenic organs and LDL cholesterol is an important source for steroidogenesis. Cholesterol must be transported into the mitochondria, where steroid hormone biosynthesis initiates. However, how LDL cholesterol is conveyed to the mitochondria is poorly defined. Here, through genome-wide small hairpin RNA screening, we find that the outer mitochondrial membrane protein phospholipase D6 (PLD6), which hydrolyses cardiolipin to phosphatidic acid, accelerates LDLR degradation. PLD6 promotes the entrance of LDL and LDLR into the mitochondria, where LDLR is degraded by mitochondrial proteases and LDL-carried cholesterol is used for steroid hormone biosynthesis. Mechanistically, the outer mitochondrial membrane protein CISD2 binds to the cytosolic tail of LDLR and tethers LDLR+ vesicles to the mitochondria. The fusogenic lipid phosphatidic acid generated by PLD6 facilitates the membrane fusion of LDLR+ vesicles with the mitochondria. This intracellular transport pathway of LDL-LDLR bypasses the lysosomes and delivers cholesterol to the mitochondria for steroidogenesis.
    DOI:  https://doi.org/10.1038/s41556-023-01160-6
  9. Shock. 2023 Jun 07.
    Severe burn-induced mitochondrial recruitment of calpain causes aberrant mitochondrial dynamics and heart dysfunction.
    Zhang Ran-Ran, Zhang Jing-Long, Li Qiao, Zhang Shu-Miao, Gu Xiao-Ming, Niu Wen, Zhou Jing-Jun, Zhou Lyu-Chen.
      ABSTRACT: Mitochondrial damage is an important cause of heart dysfunction after severe burn injury. However, the pathophysiological process remains unclear. This study aims to examine the mitochondrial dynamics in the heart, and the role of μ-calpain, a cysteine protease, in this scenario. Rats were subjected to severe burn injury treatment, and the calpain inhibitor MDL28170 was administered intravenously 1 h before or after burn injury. Rats in the burn group displayed weakened heart performance and decreased mean arterial pressure, which was accompanied by a diminishment of mitochondrial function. The animals also exhibited higher levels of calpain in mitochondria, as reflected by immunofluorescence staining and activity tests. In contrast, treatment with MDL28170 before any severe burn diminished these responses to a severe burn. Burn injury decreased the abundance of mitochondria and resulted in a lower percentage of small mitochondria and a higher percentage of large mitochondria. Furthermore, burn injury caused an increase in the fission protein DRP1 in the mitochondria and a decrease in the inner membrane fusion protein OPA1. Similarly, these alterations were also blocked by MDL28170. Of note, inhibition of calpain yielded the emergence of more elongated mitochondria along with membrane invagination in the middle of the longitude, which is an indicator of the fission process. Finally, MDL28170, administered 1 h after burn injury, preserved mitochondrial function and heart performance, and increased the survival rate. Overall, these results provided the first evidence that mitochondrial recruitment of calpain confers heart dysfunction after severe burn injury, which involves aberrant mitochondrial dynamics.
    DOI:  https://doi.org/10.1097/SHK.0000000000002159
  10. Elife. 2023 Jun 05. pii: e84204. [Epub ahead of print]12
    Calcium and bicarbonate signaling pathways have pivotal, resonating roles in matching ATP production to demand.
    Maura Greiser, Mariusz Karbowski, Aaron David Kaplan, Andrew Kyle Coleman, Nicolas Verhoeven, Carmen A Mannella, W Jonathan Lederer, Liron Boyman.
      Mitochondrial ATP production in cardiac ventricular myocytes must be continually adjusted to rapidly replenish the ATP consumed by the working heart. Two systems are known to be critical in this regulation: mitochondrial matrix Ca2+ ([Ca2+]m) and blood flow that is tuned by local ventricular myocyte metabolic signaling. However, these two regulatory systems do not fully account for the physiological range of ATP consumption observed. We report here on the identity, location, and signaling cascade of a third regulatory system -- CO2/bicarbonate. CO2 is generated in the mitochondrial matrix as a metabolic waste product of the oxidation of nutrients that powers ATP production. It is a lipid soluble gas that rapidly permeates the inner mitochondrial membrane (IMM) and produces bicarbonate (HCO3-) in a reaction accelerated by carbonic anhydrase (CA). The bicarbonate level is tracked physiologically by a bicarbonate-activated adenylyl cyclase, soluble adenylyl cyclase (sAC). Using structural Airyscan super-resolution imaging and functional measurements we find that sAC is primarily inside the mitochondria of ventricular myocytes where it generates cAMP when activated by HCO3-. Our data strongly suggest that ATP production in these mitochondria is regulated by this cAMP signaling cascade operating within the inter-membrane space (IMS) by activating local EPAC1 (Exchange Protein directly Activated by cAMP) which turns on Rap1 (Ras-related protein 1). Thus, mitochondrial ATP production is shown to be increased by bicarbonate-triggered sAC signaling through Rap1. Additional evidence is presented indicating that the cAMP signaling itself does not occur directly in the matrix. We also show that this third signaling process involving bicarbonate and sAC activates the cardiac mitochondrial ATP production machinery by working independently of, yet in conjunction with, [Ca2+]m-dependent ATP production to meet the energy needs of cellular activity in both health and disease. We propose that the bicarbonate and calcium signaling arms function in a resonant or complementary manner to match mitochondrial ATP production to the full range of energy consumption in cardiac ventricular myocytes in health and disease.
    Keywords:  biochemistry; chemical biology; molecular biophysics; rat; structural biology
    DOI:  https://doi.org/10.7554/eLife.84204
  11. Mitochondrion. 2023 Jun 03. pii: S1567-7249(23)00053-3. [Epub ahead of print]
    Megamitochondria plasticity: function transition from adaption to disease.
    Yuxing Shang, Zhanghui Li, Peiyang Cai, Wuhao Li, Ye Xu, Yangjing Zhao, Sheng Xia, Qixiang Shao, Hui Wang.
      As the cell's energy factory and metabolic hub, mitochondria are critical for ATP synthesis to maintain cellular function. Mitochondria are highly dynamic organelles that continuously undergo fusion and fission to alter their size, shape, and position, with mitochondrial fusion and fission being interdependent to maintain the balance of mitochondrial morphological changes. However, in response to metabolic and functional damage, mitochondria can grow in size, resulting in a form of abnormal mitochondrial morphology known as megamitochondria. Megamitochondria are characterized by their considerably larger size, pale matrix, and marginal cristae structure and have been observed in various human diseases. In energy-intensive cells like hepatocytes or cardiomyocytes, the pathological process can lead to the growth of megamitochondria, which can further cause metabolic disorders, cell damage and aggravates the progression of the disease. Nonetheless, megamitochondria can also form in response to short-term environmental stimulation as a compensatory mechanism to support cell survival. However, extended stimulation can reverse the benefits of megamitochondria leading to adverse effects. In this review, we will focus on the findings of the different roles of megamitochondria, and their link to disease development to identify promising clinical therapeutic targets.
    Keywords:  Megamitochondria; Mitochondria dynamics; Mitochondria morphology
    DOI:  https://doi.org/10.1016/j.mito.2023.06.001
  12. Nat Aging. 2023 Jun 05.
    Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging.
    Philip V Seegren, Logan R Harper, Taylor K Downs, Xiao-Yu Zhao, Shivapriya B Viswanathan, Marta E Stremska, Rachel J Olson, Joel Kennedy, Sarah E Ewald, Pankaj Kumar, Bimal N Desai.
      Mitochondrial dysfunction is linked to age-associated inflammation or inflammaging, but underlying mechanisms are not understood. Analyses of 700 human blood transcriptomes revealed clear signs of age-associated low-grade inflammation. Among changes in mitochondrial components, we found that the expression of mitochondrial calcium uniporter (MCU) and its regulatory subunit MICU1, genes central to mitochondrial Ca2+ (mCa2+) signaling, correlated inversely with age. Indeed, mCa2+ uptake capacity of mouse macrophages decreased significantly with age. We show that in both human and mouse macrophages, reduced mCa2+ uptake amplifies cytosolic Ca2+ oscillations and potentiates downstream nuclear factor kappa B activation, which is central to inflammation. Our findings pinpoint the mitochondrial calcium uniporter complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to systemic macrophage-mediated age-associated inflammation. The findings raise the exciting possibility that restoring mCa2+ uptake capacity in tissue-resident macrophages may decrease inflammaging of specific organs and alleviate age-associated conditions such as neurodegenerative and cardiometabolic diseases.
    DOI:  https://doi.org/10.1038/s43587-023-00436-8
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