Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues
Gemma L. PearsonEmily M. WalkerNathan LawlorAnne LietzkeVaibhav SidaralaJie ZhuTracy StromerEmma C. ReckAva M. StendahlJin LiElena Levi-D’AnconaMabelle B. PasmooijDre L. HubersAaron RenbergKawthar MohamedVishal S. ParekhIrina X. ZhangBenjamin ThompsonDeqiang ZhangSarah A. WareLeena HaatajaStephen C. J. ParkerPeter ArvanLei YinBrett A. KaufmanLeslie S. SatinLori SusselMichael L. StitzelScott A. Soleimanpour
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ABSTRACT Mitochondrial damage is a hallmark of metabolic diseases, including diabetes and metabolic dysfunction-associated steatotic liver disease, yet the consequences of impaired mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity across multiple metabolic tissues. Surprisingly, we demonstrate that defects in the mitochondrial quality control machinery, which we observe in pancreatic β cells of humans with type 2 diabetes, cause reductions of β cell mass due to dedifferentiation, rather than apoptosis. Utilizing transcriptomic profiling, lineage tracing, and assessments of chromatin accessibility, we find that targeted deficiency anywhere in the mitochondrial quality control pathway ( e.g. , genome integrity, dynamics, or turnover) activate the mitochondrial integrated stress response and promote cellular immaturity in β cells, hepatocytes, and brown adipocytes. Intriguingly, pharmacologic blockade of mitochondrial retrograde signaling in vivo restores β cell mass and identity to ameliorate hyperglycemia following mitochondrial damage. Thus, we observe that a shared mitochondrial retrograde response controls cellular identity across metabolic tissues and may be a promising target to treat or prevent metabolic disorders.Keywords:
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Abstract Retrograde signaling conceptually means the transfer of signals from semi‐autonomous cell organelles to the nucleus to modulate nuclear gene expression. A generalized explanation is that chloroplasts are highly sensitive to environmental stimuli and quickly generate signaling molecules (retrograde signals) and transport them to the nucleus through the cytosol to reprogram nuclear gene expression for cellular/metabolic adjustments to cope with environmental fluctuations. During the past decade, substantial advancements have been made in the area of retrograde signaling, including information on putative retrograde signals. Researchers have also proposed possible mechanisms for generating retrograde signals and their transmission. However, the exact mechanisms and processes responsible for transmitting retrograde signaling from the chloroplast to the nucleus remain elusive, demanding substantial attention. This review highlights strategies employed to detect retrograde signals, their possible modes of signaling to the nucleus, and their implications for cellular processes during stress conditions. The present review also summarizes the role of ROS‐mediated retrograde signaling in plastid‐nucleus communication and its functional significance in co‐coordinating the physiological profile of plant cells.
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The mitochondrion plays vital roles in various aspects of cellular metabolism, ranging from energy transduction and apoptosis to the synthesis of important molecules such as heme. Mitochondria are also centrally involved in iron metabolism, as exemplified by disruptions in mitochondrial proteins that lead to perturbations in whole-cell iron processing. Recent investigations have identified a host of mitochondrial proteins (e.g., mitochondrial ferritin; mitoferrins 1 and 2; ABCBs 6, 7, and 10; and frataxin) that may play roles in the homeostasis of mitochondrial iron. These mitochondrial proteins appear to participate in one or more processes of iron storage, iron uptake, and heme and iron–sulfur cluster synthesis. In this review, we present and critically discuss the evidence suggesting that the mitochondrion may contribute to the regulation of whole-cell iron metabolism. Further, human diseases that arise from a dysregulation of these mitochondrial molecules reveal the ability of the mitochondrion to communicate with cytosolic iron metabolism to coordinate whole-cell iron processing and to fulfill the high demands of this organelle for iron. This review highlights new advances in understanding iron metabolism in terms of novel molecular players and diseases associated with its dysregulation. Antioxid. Redox Signal. 15, 3003–3019.
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Mitochondria are well characterized by their fundamental functions in regulating cellular homeostasis, including energy and iron metabolism. These functions are essential in neurons with high metabolic demands and elongated neuronal processes. Mitochondria dynamically change morphology, localization, and activity to match neurons’ spatial and temporal demands. Mitochondrial dysfunctions have been associated with many neurological disorders. Recent studies highlight that mitochondria also act as central regulators of the neuronal response to injury. Here, we discuss important findings that support the critical regulation of mitochondrial dynamics, energy metabolism, and iron homeostasis in the repair of damaged neurons. Mitochondrial functions in energy and iron metabolism: The dynamic double-membraned organelles, mitochondria, are responsible for producing adenosine triphosphate (ATP), the energy currency of the cell, via oxidative phosphorylation. This process converts energy from glucose through a series of redox reactions at the electron transport chain of complexes located at the mitochondrial inner membrane. The nervous system is dependent on mitochondria for its high energy demands; however, the mismatch between mitochondrial biogenesis locations (cell body) and high energy consumption sites (axon and synapse) leads to a unique challenge for neurons to maintain energy homeostasis within the peripheral area of cells. The proper function of neurons also requires appropriate levels of iron, which is an essential metal for almost all organisms and involved in many oxidation/reduction reactions. In fact, depending on the cell type, mitochondria may contain up to 20–50% of total cellular iron. Since mitochondria are responsible for the biosynthesis of iron-sulfur clusters and heme, mitochondria play interrelated roles in iron homeostasis by being a critical regulator of cellular iron homeostasis and primary targets for damage in response to impaired iron homeostasis (Zeidan et al., 2021). In addition, iron is important in central nervous system (CNS) myelination, particularly the oligodendrocytes where iron is indispensable for their myelination and maturation (Levi and Taveggia, 2014). Mitochondrial transport in axon regeneration after nerve injury: Axon regeneration is one of the essential processes to recover damaged neurons with axonal disconnection. Mature neurons in the CNS have minimal axon regeneration capacity due to declines in intrinsic capacity and the presence of extrinsic factors. In contrast, neurons in the peripheral nervous system (PNS) often have a more robust regenerative capacity, although this capacity declines with age. Interestingly, studies in the PNS have highlighted that the normally stationary mitochondria become motile and move bidirectionally in response to axonal injury, raising the possibility that mitochondria could be primary responders of nerve injury. Accordingly, recent reports across species in both the CNS and PNS demonstrate that this increased proportion of motile mitochondria enhanced the axon regeneration of injured neurons. In GABAergic neurons of the nematode C. elegans, successfully regenerating axons over the injured site had significantly increased mitochondrial translocation to injured axons, resulting in high density compared to non-regenerating neurons. In contrast, neurons with failed axon regeneration contain low mitochondrial density in injured axons. Inhibition or activation of mitochondrial transport into the axon by targeting Miro, a conserved mitochondrial trafficking regulator, leads to corresponding changes in axonal regenerative capacity with a positive correlation (Han et al., 2016). Manipulating mitochondrial motility in vertebrates is also associated with axon regeneration capacity (Cartoni et al., 2016; Zhou et al., 2016; Xu et al., 2017). For example, in the zebrafish CNS, mitochondrial motility is positively correlated with axon regeneration (Xu et al., 2017). Pharmacological manipulation with dibutyryl cyclic adenosine monophosphate, a structural analog of endogenous cyclic adenosine monophosphate, was shown to enhance regeneration in zebrafish axons and increase mitochondrial motility (Xu et al., 2017). In adult murine retinal ganglion cells, the Armadillo Repeat Containing X-Linked 1 (Armcx1) protein localizes to mitochondria, interacts with Miro, and increases mitochondrial transport. Importantly, overexpression of Armcx1 protects axotomized neurons from cell death and promotes axon regeneration after optic nerve injury depending on its mitochondrial localization (Cartoni et al., 2016). In contrast, Armcx1 knockdown undermines both neuronal survival and axon regeneration in the PTEN knockout condition with high regenerative capacity. In addition, syntaphilin (SNPH) is an axonal mitochondria-anchoring protein whose levels increase as neurons mature. Knock-out of SNPH in mice results in ~70% increase of axonal mitochondria and is associated with the clearance of injured mitochondria and replacement with healthy mitochondria after sciatic nerve injury (Zhou et al., 2016). Thus, decreased mitochondrial transport as an intrinsic factor limiting regenerative capacity in mature neurons could be bypassed through genetic or pharmacological means. It remains incompletely understood how nerve injury affects mitochondrial transport in the injured axons. In the C. elegans GABAergic neurons, the dual-leucine zipper kinase 1 (DLK-1) mitogen activated protein kinase pathway, a conserved axon regeneration regulator, promotes mitochondria trafficking within axons (Figure 1A), indicating that specific injury signals could be involved (Han et al., 2016). The ability of DLK-1 signaling to increase mitochondrial trafficking was largely dependent on the CEBP-1 transcription factor suggesting transcriptional regulation of target genes is involved. However, in neurons lacking DLK-1 signaling, the increase in mitochondrial density was reduced but not eliminated suggesting other unknown injury pathways working in parallel to link injury to mitochondria (Han et al., 2016). In retinal ganglion cells, Armcx1 was identified as an up-regulated gene in the PTEN knock-out mice, an axon regeneration inhibitor in both the PNS and CNS. However, it remains to be determined if PTEN signaling regulates Armcx1 (Cartoni et al., 2016). Recent studies indicate that the phosphorylation status of SNPH regulated by protein kinase B (AKT) growth signaling and subsequent P21-activated kinase 5 activation may act as an axonal mitochondrial signaling pathway that remobilizes damaged mitochondria in response to ischemic injury (Huang et al., 2021; Figure 1A). P21-activated kinase 5 is a brain mitochondrial kinase that declines in expression as neurons mature, but upon axonal injury/ischemia is locally synthesized and activated while AKT signaling further potentiates P21-activated kinase 5 activity.Figure 1: The multifaceted roles of mitochondria in neuronal recovery after injury.(A) DLK-1 and AKT signaling promote mitochondrial trafficking. The DLK-1 signaling is required to promote mitochondrial positioning to the injured axon, while AKT phosphorylates syntaphilin via PAK5 and releases stalled mitochondria. Additionally, Amrxc-1 binds to Miro, which along with Milton and kinesin, increases anterograde mitochondrial transport to supply ATP for neuronal repair. (B) AKT activation leads to a reduction in cellular iron concentration by downregulating transferrin levels and upregulating ferroportin levels, which result in a decrease in cellular iron import and an increase in cellular iron export, respectively. Additionally, inhibition of ferroptosis (iron-induced cell death) is another way to promote injury repair. AKT: Protein kinase B; ATP: adenosine triphosphate; DLK-1: dual-leucine zipper kinase 1; MAPKKK: mitogen activated protein (MAP) kinase kinase kinase; PAK5: P21-activated kinase 5; TF: transferrin. This figure was created with BioRender.com.Mitochondrial energy metabolism in axon regeneration after nerve injury: Axon regeneration involves multiple steps, including membrane sealing of the injured axon, activation of signaling pathways to promote transcription and translation of pro-growth genes, formation of functional growth cones, and cytoskeletal remodeling, all of which require copious amounts of energy. Not surprisingly, the cellular energy factories mitochondria play a pivotal role in providing the energy necessary for axon regrowth (Cartoni et al., 2016; Han et al., 2016; Zhou et al., 2016; Xu et al., 2017). In the C. elegans GABAergic neurons, mutations in the core components of the mitochondrial electron transport complex decrease axon regeneration capacity (Han et al., 2016). In the sciatic nerve of mammals, nerve injury depolarizes mitochondria membrane potential and results in a local energy deficit (Zhou et al., 2016). Increased mitochondrial trafficking suppressed the energy deficit along with enhanced axon regeneration capacity (Zhou et al., 2016). Supplying ATP to SNPH-deficient neurons was able to partially recover suppression of axon regrowth (Zhou et al., 2016). Since ATP has a limited diffusion capacity throughout the axon, increased mitochondrial trafficking is likely more efficient in providing ATP to the peripheral axon from the cell body. Although providing additional ATP could be one strategy to treat injured axons and bypass the issue of motility, mitochondria might be the more suitable therapeutic option, given that the rapid degradation of ATP limits its efficacy. As a potential alternative to ATP, creatine has been used as an energetic facilitator to promote the regeneration of axons after spinal cord injury in mice (Han et al., 2020). Creatine elevates creatine kinase activity and restores ATP independent of mitochondrial transport. The combination of genetically knocking down SNPH and administering creatine further enhanced corticospinal tract regenerative capacity in the Snph–/– mice (Huang et al., 2021). Mitochondrial iron homeostasis in axon regeneration after nerve injury: Besides their critical functions in energy homeostasis, mitochondria’s regulation of cellular iron homeostasis also plays a crucial role in the neuronal response to injury. Recent studies reported that peripheral nerve injury led to an increase in the expression levels of transferrin (iron importer) and transferrin receptor, and a decrease in the expression levels of ferroportin (iron exporter). Moreover, heme oxygenase-1 is induced during nerve regeneration in order to catalyze the release of iron from heme and this is accompanied by an increase in transferrin receptor 1 suggesting recycling of iron for use in the regeneration process. All these changes thereby increase intracellular iron levels and eventually, if not properly regulated, can lead to cellular iron overload. This will increase oxidative stress and jeopardize the mitochondrial ability to produce the ATP required for injury repair. On the other hand, interestingly, transferrin in the PNS is thought to be a pro-differentiation factor and has a role in nerve differentiation, regeneration, and myelination in addition to its role in iron transport (Levi and Taveggia, 2014). Given that iron is a vital co-factor for ATP production in mitochondria, providing an adequate level of iron to mitochondria located in peripheral axons far from the cell body is important for neuronal recovery after injury, whereas iron chelation can impair nerve degeneration. Recent studies indicate that Schwann cells conceivably supply iron to neurons with long axons, such as the sciatic nerve (Mietto et al., 2021). Importantly, the iron supplied by Schwann cells to long axons is vital for proper axon regeneration and mobility recovery after injury in the PNS. Disrupted iron homeostasis diminished mitochondrial positioning to injured axons and broadly decreased the expression of mitochondrial fusion and transport regulators, including Miro and Armcx1 (Mietto et al., 2021). Interestingly, the activation of AKT by iron signaling could lead to a reduction of cellular iron content and protect neurons from injury. This is achieved by decreasing the transferrin receptor-mediated iron uptake and upregulating the ferroportin-mediated iron efflux (Figure 1B). The reduction in the cellular iron concentration and restoration of iron homeostasis eventually lead to restoration of mitochondrial health and function (Hao et al., 2016). Recently, the iron-dependent programmed cell death ferroptosis has been shown to negatively affect neuronal function, survival, and plasticity during nerve injury (Feng et al., 2021; Figure 1B). Ferroptosis is characterized by an iron-induced increase in lipid reactive oxygen species and, eventually, decreased cellular glutathione reserve and dampened activity of glutathione peroxidase 4, all of which contribute to the distorted mitochondrial morphology and impaired function, and subsequent cellular death (Zeidan et al., 2021). In fact, ferroptosis inhibition has been suggested as a potential therapeutic for nerve injury. Ferrostatin-1, a ferroptosis inhibitor, was able to reverse the increase of the iron content in injured rat spinal cords. Remarkably, ferrostatin-1 increases glutathione peroxidase 4 expression, induces neuron and astrocyte activation, alleviates the associated pain, and promotes injury healing in rats (Wang et al., 2021). Collectively, understanding how mitochondria relate to declines in intrinsic capacity for axon regrowth is critical to successful axon regeneration. Mitochondria sit as hubs for interconnected pathways between energy and iron homeostasis and present as attractive therapeutic targets to promote neuronal recovery following injury. The authors would like to acknowledge and apologize that not all relevant literature has been cited due to space constraints. This work was supported by grants from the National Institute on Aging (AG063766 and AG028740 to RX, AG066654 to SMH, T32AG062728 to TM), the American Cancer Society (RSG-17-171-01-DMC to RX), and the American Federation for Aging Research (AGR DT 07-2502019 and AGR DTD 09-15-2021 to SMH). Open peer reviewer:Andrew William James Paterson, Leeds Beckett University, UK. P-Reviewer: Paterson AWJ; C-Editors: Zhao M, Liu WJ, Wang Lu; T-Editor: Jia Y
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Normal cellular physiology is critically dependent on numerous mitochondrial activities including energy conversion, cofactor and precursor metabolite synthesis, and regulation of ion and redox homeostasis. Advances in mitochondrial research during the last two decades provides solid evidence that these organelles are deeply integrated with the rest of the cell and multiple mechanisms are in place to monitor and communicate functional states of mitochondria. In many cases, however, the exact molecular nature of various mitochondria-to-cell communication pathways is only beginning to emerge. Here, we review various signals emitted by distressed or dysfunctional mitochondria and the stress-responsive pathways activated in response to these signals in order to restore mitochondrial function and promote cellular survival.
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哺乳動物には,2種類のゲノム,核DNAとミトコンドリアDNA(mtDNA)が存在している.mtDNAの遺伝様式は,母性遺伝と急調分離に代表されるように,核DNAとは大きく異なる. mtDNAは古くから母性遺伝をすることが信じられてきた.なぜなら,哺乳動物では卵に存在するmtDNAコピー数が精子よりも103-4倍多く,極微量の精子由来mtDNAが次世代へと伝達されることが考えにくかったためである.しかし,当時の技術ではこの極微量の"精子由来のmtDNA"が検出されず,父親由来のmtDNAが子孫へ伝達している可能性が残されていた.その後,高感度なPCR法を用いることで,マウス精子のmtDNAが前核期後期までに消失することが示され,幾つかの特殊な事例を除き,mtDNAは完全に母性遺伝することが,実験的に証明された.形態学的解析からもマウスでは受精時に卵細胞質内に侵入した精子由来ミトコンドリアが2細胞期までにほぼ消失する様子が観察されており,ユビキチン‐プロテアソーム分解系の関与が報告されている. 一方,急調分離とはmtDNAの状態がヘテロプラズミーからホモプラズミーへ速やかに移行する遺伝現象である.mtDNAは体細胞では103-4コピー存在しており,核DNAの約1-10倍も変異を起こしやすい.このことから,ヘテロプラズミーの方がホモプラズミーより起こりやすいことが想定されるが,実際はその逆で一つの細胞に複数のmtDNA分子種が存在することは極めて稀である.このホモプラズミー維持の機構が「ボトルネック効果」であり,これまで「雌性生殖系の細胞中のmtDNA数が極端に減少する」としたモデルが広く受入れられてきた.ところが,実際にmtDNA分子数を我々が測定するとそのコピー数に極端な減少は無く,ホモプラズミーの維持はコピー数減少以外の機構によってmtDNAの分離単位の実効数が小さくなるためと考えられる.
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How do yeast sense mitochondrial dysfunction? – INTRODUCTION In present-day eukaryotes mitochondria play multiple roles such as oxidative phosphorylation, Fe-S clusters biosynthesis, thermogenesis and others (see for review ). Some special features of mitochondria make them a unique cellular signaling center. First, mitochondria have two compartments separated from the cytoplasm. Outer membrane is impermeable for molecules with molecular weight above 8 KDa , (...)
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