Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons (MNs) and subsequent muscle weakness. These pathological features are associated with numerous cellular changes, including alteration in mitochondrial morphology and function. However, the molecular mechanisms associating mitochondrial structure with ALS pathology are poorly understood. In this study, we found that Dynamin-related protein 1 (Drp1) was dephosphorylated in several ALS models, including those with SOD1 and TDP-43 mutations, and the dephosphorylation was mediated by the pathological induction of protein phosphatase 1 (PP1) activity in these models. Suppression of the PP1-Drp1 cascade effectively prevented ALS-related symptoms, including mitochondrial fragmentation, mitochondrial complex I impairment, axonal degeneration, and cell death, in primary neuronal culture models, iPSC-derived human MNs, and zebrafish models in vivo. These results suggest that modulation of PP1-Drp1 activity may be a therapeutic target for multiple pathological features of ALS

C9ORF72-ALS/FTD-associated poly(GR) binds Atp5a1 and compromises mitochondrial function in vivo

The GGGGCC repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is not known which dysregulated molecular pathways are primarily responsible for disease initiation or progression. We established an inducible mouse model of poly(GR) toxicity in which (GR)80 gradually accumulates in cortical excitatory neurons. Low-level poly(GR) expression induced FTD/ALS-associated synaptic dysfunction and behavioral abnormalities, as well as age-dependent neuronal cell loss, microgliosis and DNA damage, probably caused in part by early defects in mitochondrial function. Poly(GR) bound preferentially to the mitochondrial complex V component ATP5A1 and enhanced its ubiquitination and degradation, consistent with reduced ATP5A1 protein level in both (GR)80 mouse neurons and patient brains. Moreover, inducing ectopic Atp5a1 expression in poly(GR)-expressing neurons or reducing poly(GR) level in adult mice after disease onset rescued poly(GR)-induced neurotoxicity. Thus, poly(GR)-induced mitochondrial defects are a major driver of disease initiation in C9ORF72-related ALS/FTD

Organometallic Iridium(III) Complex Sensitized Ternary Hybrid Photocatalyst for CO2 to CO Conversion

A series of heteroleptic iridium(III) complexes functionalized with two phosphonic acid (-PO3H2) groups ((IrP)-Ir-dfppy, (IrP)-Ir-ppy, (IrP)-Ir-btp, and (IrP)-Ir-piq) were prepared and anchored onto rhenium(I) catalyst (ReP)-loaded TiO2 particles (TiO2/ReP) to build up a new IrP-sensitized TiO2 photocatalyst system (IrP/TiO2/ReP). The photosensitizing behavior of the IrP series was examined within the IrP/TiO2/ReP platform for the photocatalytic conversion of CO2 into CO. The four IrP-based ternary hybrids showed increased conversion activity and durability than that of the corresponding homo- (IrP+ReP) and heterogeneous (IrP+TiO2/ReP) mixed systems. Among the four IrP/TiO2/ReP photocatalysts, the low-energy-light (>500 nm) activated (IrP)-Ir-piq immobilized ternary system ((IrP)-Ir-piq/TiO2/ReP) exhibited the most durable conversion activity, giving a turnover number of >= 730 for 170 h. A similar kinetic feature observed through time-resolved photoluminescence measurements of both (IrP)-Ir-btp/TiO2 and TiO2-free (IrP)-Ir-btp films suggests that the net electron flow in the ternary hybrid proceeds dominantly through a reductive quenching mechanism, unlike the oxidative quenching route of typical dye/TiO2-based photolysis.11Nsciescopu

Photophysics and Excited-State Properties of Cyclometalated Iridium(III)–Platinum(II) and Iridium(III)–Iridium(III) Bimetallic Complexes Bridged by Dipyridylpyrazine

We investigated the electrochemical and excited-state properties of 2,3-bis­(2-pyridyl)­pyrazine (dpp)-bridged bimetallic complexes, (L)₂Ir-dpp-PtCl [<b>1</b>, L = 2-(4′,6′-difluorophenyl)­pyridinato-<i>N</i>,<i>C</i>² (dfppy); <b>2</b>, L = 2-phenylpyridinato-<i>N</i>,<i>C</i>² (ppy)] and [(L)₂Ir]₂(dpp) [<b>3</b>, L = dfppy; <b>4</b>, L = ppy] compared to monometallic complexes, (L)₂Ir-dpp (<b>5</b>, L = dfppy; <b>6</b>, L = ppy) and dpp-PtCl (dpp-Pt^IICl₂; <b>7</b>). The single-crystal X-ray crystallographic structures of <b>1</b>, <b>3</b>, <b>5</b>, and <b>6</b> showed that <b>1</b> and <b>3</b> have approximately coplanar structures of the dpp unit, while the noncoordinated pyridine ring of dpp in <b>5</b> and <b>6</b> is largely twisted with respect to the pyrazine ring. We found that the properties of the bimetallic complex significantly depended on the electronic and geometrical modulations of each fragment: (1) electronic structure of the main L (C^N) ligand in an iridium chromophore (L = dfppy or ppy) and (2) planarity of the bridging ligand (dpp). Their electrochemical and photophysical properties revealed that efficient electron-transfer processes predominated in the bimetallic systems regardless of the second metal participation. The low efficiencies of photoluminescence of dpp-bridged Ir–Pt and Ir–Ir bimetallic complexes (<b>1</b>–<b>4</b>) could be explained by assuming the involvement of crossing to platinum- and iridium-based d–d states from the emissive state. Such stereochemical and electronic situations around dpp allowed thermally activated crossing to platinum- and iridium-based d–d states from the emissive triplet metal-to-ligand charge-transfer (³MLCT) state, followed by cleavage of the dpp-Pt and (L)₂Ir-dpp bonds. The transient absorption study further confirmed that the planarity of the dpp bridging ligand, which was defined as the magnitude of tilt between the pyridine ring and pyrazine, had a direct correlation with the degree of nonradiative decay from the emissive iridium-based ³MLCT to the Ir d–d or Pt d–d state, leading to photoinduced dissociation of bimetallic complexes. From the dissociation pattern of metal complexes analyzed after photoirradiation, we found that their dissociation pathways were directly related to the quenching direction (either Ir d–d or Pt d–d) with a significant dependency on the relative ³MLCT levels of the (L)₂Ir-dpp component

Photophysics and Excited-State Properties of Cyclometalated Iridium(III)–Platinum(II) and Iridium(III)–Iridium(III) Bimetallic Complexes Bridged by Dipyridylpyrazine

We investigated the electrochemical and excited-state properties of 2,3-bis­(2-pyridyl)­pyrazine (dpp)-bridged bimetallic complexes, (L)₂Ir-dpp-PtCl [<b>1</b>, L = 2-(4′,6′-difluorophenyl)­pyridinato-<i>N</i>,<i>C</i>² (dfppy); <b>2</b>, L = 2-phenylpyridinato-<i>N</i>,<i>C</i>² (ppy)] and [(L)₂Ir]₂(dpp) [<b>3</b>, L = dfppy; <b>4</b>, L = ppy] compared to monometallic complexes, (L)₂Ir-dpp (<b>5</b>, L = dfppy; <b>6</b>, L = ppy) and dpp-PtCl (dpp-Pt^IICl₂; <b>7</b>). The single-crystal X-ray crystallographic structures of <b>1</b>, <b>3</b>, <b>5</b>, and <b>6</b> showed that <b>1</b> and <b>3</b> have approximately coplanar structures of the dpp unit, while the noncoordinated pyridine ring of dpp in <b>5</b> and <b>6</b> is largely twisted with respect to the pyrazine ring. We found that the properties of the bimetallic complex significantly depended on the electronic and geometrical modulations of each fragment: (1) electronic structure of the main L (C^N) ligand in an iridium chromophore (L = dfppy or ppy) and (2) planarity of the bridging ligand (dpp). Their electrochemical and photophysical properties revealed that efficient electron-transfer processes predominated in the bimetallic systems regardless of the second metal participation. The low efficiencies of photoluminescence of dpp-bridged Ir–Pt and Ir–Ir bimetallic complexes (<b>1</b>–<b>4</b>) could be explained by assuming the involvement of crossing to platinum- and iridium-based d–d states from the emissive state. Such stereochemical and electronic situations around dpp allowed thermally activated crossing to platinum- and iridium-based d–d states from the emissive triplet metal-to-ligand charge-transfer (³MLCT) state, followed by cleavage of the dpp-Pt and (L)₂Ir-dpp bonds. The transient absorption study further confirmed that the planarity of the dpp bridging ligand, which was defined as the magnitude of tilt between the pyridine ring and pyrazine, had a direct correlation with the degree of nonradiative decay from the emissive iridium-based ³MLCT to the Ir d–d or Pt d–d state, leading to photoinduced dissociation of bimetallic complexes. From the dissociation pattern of metal complexes analyzed after photoirradiation, we found that their dissociation pathways were directly related to the quenching direction (either Ir d–d or Pt d–d) with a significant dependency on the relative ³MLCT levels of the (L)₂Ir-dpp component

Photophysics and Excited-State Properties of Cyclometalated Iridium(III)–Platinum(II) and Iridium(III)–Iridium(III) Bimetallic Complexes Bridged by Dipyridylpyrazine

We investigated the electrochemical and excited-state properties of 2,3-bis­(2-pyridyl)­pyrazine (dpp)-bridged bimetallic complexes, (L)₂Ir-dpp-PtCl [<b>1</b>, L = 2-(4′,6′-difluorophenyl)­pyridinato-<i>N</i>,<i>C</i>² (dfppy); <b>2</b>, L = 2-phenylpyridinato-<i>N</i>,<i>C</i>² (ppy)] and [(L)₂Ir]₂(dpp) [<b>3</b>, L = dfppy; <b>4</b>, L = ppy] compared to monometallic complexes, (L)₂Ir-dpp (<b>5</b>, L = dfppy; <b>6</b>, L = ppy) and dpp-PtCl (dpp-Pt^IICl₂; <b>7</b>). The single-crystal X-ray crystallographic structures of <b>1</b>, <b>3</b>, <b>5</b>, and <b>6</b> showed that <b>1</b> and <b>3</b> have approximately coplanar structures of the dpp unit, while the noncoordinated pyridine ring of dpp in <b>5</b> and <b>6</b> is largely twisted with respect to the pyrazine ring. We found that the properties of the bimetallic complex significantly depended on the electronic and geometrical modulations of each fragment: (1) electronic structure of the main L (C^N) ligand in an iridium chromophore (L = dfppy or ppy) and (2) planarity of the bridging ligand (dpp). Their electrochemical and photophysical properties revealed that efficient electron-transfer processes predominated in the bimetallic systems regardless of the second metal participation. The low efficiencies of photoluminescence of dpp-bridged Ir–Pt and Ir–Ir bimetallic complexes (<b>1</b>–<b>4</b>) could be explained by assuming the involvement of crossing to platinum- and iridium-based d–d states from the emissive state. Such stereochemical and electronic situations around dpp allowed thermally activated crossing to platinum- and iridium-based d–d states from the emissive triplet metal-to-ligand charge-transfer (³MLCT) state, followed by cleavage of the dpp-Pt and (L)₂Ir-dpp bonds. The transient absorption study further confirmed that the planarity of the dpp bridging ligand, which was defined as the magnitude of tilt between the pyridine ring and pyrazine, had a direct correlation with the degree of nonradiative decay from the emissive iridium-based ³MLCT to the Ir d–d or Pt d–d state, leading to photoinduced dissociation of bimetallic complexes. From the dissociation pattern of metal complexes analyzed after photoirradiation, we found that their dissociation pathways were directly related to the quenching direction (either Ir d–d or Pt d–d) with a significant dependency on the relative ³MLCT levels of the (L)₂Ir-dpp component