bims-mignad 2024-09-08 papers

Issue of 2024‒09‒08
five papers selected by
Melisa Emel Ermert, Amsterdam UMC

FEBS Lett. 2024 Sep 03.

Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.

The opening of the mitochondrial permeability transition pore (PTP), a Ca2+-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.

Keywords: F‐ATP synthase; cyclophilin D; ferroptosis; mitochondrial carrier homolog 2; mitochondrial permeability transition

DOI: https://doi.org/10.1002/1873-3468.15008

Nat Metab. 2024 Sep 02.

Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome.

Ritsuko Nakai, Stella Varnum, Rachael L Field, Henyun Shi, Rocky Giwa, Wentong Jia, Samantha J Krysa, Eva F Cohen, Nicholas Borcherding, Russell P Saneto, Rick C Tsai, Masashi Suganuma, Hisashi Ohta, Takafumi Yokota, Jonathan R Brestoff.

Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1-3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4-/- peritoneal macrophages4-7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10-12, brain13-15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4-/- mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4-/- mice, whereas mitochondria from Ndufs4-/- mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4-/- mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.

DOI: https://doi.org/10.1038/s42255-024-01125-5

Biochim Biophys Acta Mol Basis Dis. 2024 Aug 30. pii: S0925-4439(24)00481-2. [Epub ahead of print]1870(8): 167487

Nicotinamide riboside kinase 2: A unique target for skeletal muscle and cardiometabolic diseases.

Firdos Ahmad, Rizwan Qaisar.

Myopathy leads to skeletal and cardiac muscle degeneration which is a major cause of physical disability and heart failure. Despite the therapeutic advancement the prevalence of particularly cardiac diseases is rising at an alarming rate and novel therapeutic targets are required. Nicotinamide riboside kinase-2 (NRK-2 or NMRK2) is a muscle-specific β1-integrin binding protein abundantly expressed in the skeletal muscle while only a trace amount is detected in the healthy cardiac muscle. The level in cardiac tissue is profoundly upregulated under pathogenic conditions such as ischemia and hypertension. NRK-2 was initially identified to regulate myoblast differentiation and to enhance the levels of NAD+, an important coenzyme that potentiates cellular energy production and stress resilience. Recent advancement has shown that NRK-2 critically regulates numerous cellular and molecular processes under pathogenic conditions to modulate the disease severity. Therefore, given its restricted expression in the cardiac and skeletal muscle, NRK-2 may serve as a unique therapeutic target. In this review, we provided a comprehensive overview of the diverse roles of NRK-2 played in different cardiac and muscular diseases and discussed the underlying molecular mechanisms in detail. Moreover, this review precisely examined how NRK-2 regulates metabolism in cardiac muscle, and how dysfunctional NRK-2 is associated with energetic deficit and impaired muscle function, manifesting various cardiac and skeletal muscle disease conditions.

Keywords: Cardiac; Cell signaling; Metabolism; Myopathy; NMRK2; Skeletal muscle

DOI: https://doi.org/10.1016/j.bbadis.2024.167487

Sci Rep. 2024 09 04. 14(1): 20575

The compartment-specific manipulation of the NAD+/NADH ratio affects the metabolome and the function of glioblastoma.

Myunghoon Lee, Jae Hong Yoo, Inseo Kim, Sinbeom Kang, Wonsik Lee, Sungjin Kim, Kyung-Seok Han.

Glioblastoma multiforme (GBM) is the most aggressive type of cancer in the brain and has an inferior prognosis because of the lack of suitable medicine, largely due to its tremendous invasion. GBM has selfish metabolic pathways to promote migration, invasion, and proliferation compared to normal cells. Among various metabolic pathways, NAD (nicotinamide adenine dinucleotide) is essential in generating ATP and is used as a resource for cancer cells. LbNOX (Lactobacillus brevis NADH oxidase) is an enzyme that can directly manipulate the NAD+/NADH ratio. In this study, we found that an increased NAD+/NADH ratio by LbNOX or mitoLbNOX reduced intracellular glutamate and calcium responses and reduced invasion capacity in GBM. However, the invasion was not affected in GBM by rotenone, an ETC (Electron Transport Chain) complex I inhibitor, or nicotinamide riboside, a NAD+ precursor, suggesting that the crucial factor is the NAD+/NADH ratio rather than the absolute quantity of ATP or NAD+ for the invasion of GBM. To develop a more accurate and effective GBM treatment, our findings highlight the importance of developing a new medicine that targets the regulation of the NAD+/NADH ratio, given the current lack of effective treatment options for this brain cancer.

Keywords: LbNOX; Glioblastoma; Glutamate; Invasion; NAD+/NADH

DOI: https://doi.org/10.1038/s41598-024-71462-8

J Nutr Sci Vitaminol (Tokyo). 2024 ;70(4): 295-304

The Rate of NAD+ Breakdown Is Maintained Constant against Deletion or Overexpression of NAD+-Degrading Enzymes in Mammalian Cells.

Nobumasa Hara, Harumi Osago, Mineyoshi Hiyoshi, Mikiko Kobayashi-Miura.

Cellular NAD+ is continuously degraded and synthesized under resting conditions. In mammals, NAD+ synthesis is primarily initiated from nicotinamide (Nam) by Nam phosphoribosyltransferase, whereas poly(ADP-ribose) polymerase 1 (PARP1) and 2 (PARP2), sirtuin1 (SIRT1), CD38, and sterile alpha and TIR motif containing 1 (SARM1) are involved in NAD+ breakdown. Using flux analysis with 2H-labeled Nam, we found that when mammalian cells were cultured in the absence of Nam, cellular NAD+ levels were maintained and NAD+ breakdown was completely suppressed. In the presence of Nam, the rate of NAD+ breakdown (RB) did not significantly change upon PARP1, PARP2, SIRT1, or SARM1 deletion, whereas stable expression of CD38 did not increase RB. However, RB in PARP1-deleted cells was much higher compared with that in wild-type cells, in which PARP1 activity was blocked with a selective inhibitor. In contrast, RB in CD38-overexpressing cells in the presence of a specific CD38 inhibitor was much lower compared with that in control cells. The results indicate that PARP1 deletion upregulates the activity of other NADases, whereas CD38 expression downregulates the activity of endogenous NADases, including PARP1 and PARP2. The rate of cellular NAD+ breakdown and the resulting NAD+ concentration may be maintained at a constant level, despite changes in the NAD+-degrading enzyme expression, through the compensatory regulation of NADase activity.

Keywords: CD38; NAD+ breakdown; PARP1; PARP2; SARM1; SIRT1

DOI: https://doi.org/10.3177/jnsv.70.295