bims-mikwok 2021-09-26 papers

Mitochondrion. 2021 Sep 15. pii: S1567-7249(21)00121-5. [Epub ahead of print]

Mitofusin 2: A Link Between Mitochondrial Function and Substrate Metabolism?

Mitochondria are dynamic, interactive organelles that connect cellular signaling and whole-cell homeostasis. This "mitochatting" allows the cell to receive information about the mitochondria's condition before accommodating energy demands. Mitofusin 2 (Mfn2), an outer mitochondrial membrane fusion protein specializes in mediating mitochondrial homeostasis. Early studies defined the biological significance of Mfn2, latter studies highlighted its role in substrate metabolism. However, determining Mfn2 potential to contribute to energy homeostasis needs study. This review summarizes current literature on mitochondrial metabolic processes, dynamics, and evidence of interactions among Mfn2 and regulatory processes that may link Mfn2's role in maintaining mitochondrial function and substrate metabolism.

Keywords: fatty acid oxidation; fission; fusion; glycolysis; mitochondrial dynamics; mitophagy

DOI: https://doi.org/10.1016/j.mito.2021.09.003

EMBO J. 2021 Sep 20. e108648

Ablation of mitochondrial DNA results in widespread remodeling of the mitochondrial complexome.

Sergio Guerrero-Castillo, Joeri van Strien, Ulrich Brandt, Susanne Arnold.

So-called ρ0 cells lack mitochondrial DNA and are therefore incapable of aerobic ATP synthesis. How cells adapt to survive ablation of oxidative phosphorylation remains poorly understood. Complexome profiling analysis of ρ0 cells covered 1,002 mitochondrial proteins and revealed changes in abundance and organization of numerous multiprotein complexes including previously not described assemblies. Beyond multiple subassemblies of complexes that would normally contain components encoded by mitochondrial DNA, we observed widespread reorganization of the complexome. This included distinct changes in the expression pattern of adenine nucleotide carrier isoforms, other mitochondrial transporters, and components of the protein import machinery. Remarkably, ablation of mitochondrial DNA hardly affected the complexes organizing cristae junctions indicating that the altered cristae morphology in ρ0 mitochondria predominantly resulted from the loss of complex V dimers required to impose narrow curvatures to the inner membrane. Our data provide a comprehensive resource for in-depth analysis of remodeling of the mitochondrial complexome in response to respiratory deficiency.

Keywords: OXPHOS; complexome profiling; mitochondria; mtDNA; rho0 cells

DOI: https://doi.org/10.15252/embj.2021108648

Elife. 2021 Sep 21. pii: e68394. [Epub ahead of print]10

Fine-tuned repression of Drp1 driven mitochondrial fission primes a 'stem/progenitor-like state' to support neoplastic transformation.

Brian Spurlock, Danitra Parker, Malay Kumar Basu, Anita Hjelmeland, Sajina Gc, Shanrun Liu, Gene P Siegal, Alan Gunter, Aida Moran, Kasturi Mitra.

Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks'; level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation.

Keywords: cancer biology; cell biology; mouse

DOI: https://doi.org/10.7554/eLife.68394

FASEB J. 2021 Oct;35(10): e21933

Skeletal muscle type-specific mitochondrial adaptation to high-fat diet relies on differential autophagy modulation.

Pablo E Morales, Matías Monsalves-Álvarez, Satya Murthy Tadinada, Matthew P Harris, Andrea Ramírez-Sagredo, Jafet Ortiz-Quintero, Mayarling Francisca Troncoso, Nicole De Gregorio, Ximena Calle, Renata O Pereira, Vitor A Lira, Alejandra Espinosa, E Dale Abel, Sergio Lavandero.

In obesity, skeletal muscle mitochondrial activity changes to cope with increased nutrient availability. Autophagy has been proposed as an essential mechanism involved in the regulation of mitochondrial metabolism. Still, the contribution of autophagy to mitochondrial adaptations in skeletal muscle during obesity is unknown. Here, we show that in response to high-fat diet (HFD) feeding, distinct skeletal muscles in mice exhibit differentially regulated autophagy that may modulate mitochondrial activity. We observed that after 4 and 40 weeks of high-fat diet feeding, OXPHOS subunits and mitochondrial DNA content increased in the oxidative soleus muscle. However, in gastrocnemius muscle, which has a mixed fiber-type composition, the mitochondrial mass increased only after 40 weeks of HFD feeding. Interestingly, fatty acid-supported mitochondrial respiration was enhanced in gastrocnemius, but not in soleus muscle after a 4-week HFD feeding. This increased metabolic profile in gastrocnemius was paralleled by preserving autophagy flux, while autophagy flux in soleus was reduced. To determine the role of autophagy in this differential response, we used an autophagy-deficient mouse model with partial deletion of Atg7 specifically in skeletal muscle (SkM-Atg7+/- mice). We observed that Atg7 reduction resulted in diminished autophagic flux in skeletal muscle, alongside blunting the HFD-induced increase in fatty acid-supported mitochondrial respiration observed in gastrocnemius. Remarkably, SkM-Atg7+/- mice did not present increased mitochondria accumulation. Altogether, our results show that HFD triggers specific mitochondrial adaptations in skeletal muscles with different fiber type compositions, and that Atg7-mediated autophagy modulates mitochondrial respiratory capacity but not its content in response to an obesogenic diet.

Keywords: Atg7; fatty acids; obesity; skeletal muscle fiber

DOI: https://doi.org/10.1096/fj.202001593RR

Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00692-4. [Epub ahead of print]81(18): 3803-3819.e7

Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK.

Mitochondrial dynamics regulated by mitochondrial fusion and fission maintain mitochondrial functions, whose alterations underline various human diseases. Here, we show that inositol is a critical metabolite directly restricting AMPK-dependent mitochondrial fission independently of its classical mode as a precursor for phosphoinositide generation. Inositol decline by IMPA1/2 deficiency elicits AMPK activation and mitochondrial fission without affecting ATP level, whereas inositol accumulation prevents AMPK-dependent mitochondrial fission. Metabolic stress or mitochondrial damage causes inositol decline in cells and mice to elicit AMPK-dependent mitochondrial fission. Inositol directly binds to AMPKγ and competes with AMP for AMPKγ binding, leading to restriction of AMPK activation and mitochondrial fission. Our study suggests that the AMP/inositol ratio is a critical determinant for AMPK activation and establishes a model in which AMPK activation requires inositol decline to release AMPKγ for AMP binding. Hence, AMPK is an inositol sensor, whose inactivation by inositol serves as a mechanism to restrict mitochondrial fission.

Keywords: AMP; AMPK; IMPA1; energy stress; glucose deprivation; inosiotl sensor; inositol; inositol/AMP ratio; mitochondrial fission; mitocondrial dynamics

DOI: https://doi.org/10.1016/j.molcel.2021.08.025

iScience. 2021 Sep 24. 24(9): 103038

In situ observation of mitochondrial biogenesis as the early event of apoptosis.

Chang-Sheng Shao, Xiu-Hong Zhou, Yu-Hui Miao, Peng Wang, Qian-Qian Zhang, Qing Huang.

Mitochondrial biogenesis is a cell response to external stimuli which is generally believed to suppress apoptosis. However, during the process of apoptosis, whether mitochondrial biogenesis occurs in the early stage of the apoptotic cells remains unclear. To address this question, we constructed the COX8-EGFP-ACTIN-mCherry HeLa cells with recombinant fluorescent proteins respectively tagged on the nucleus and mitochondria and monitored the mitochondrial changes in the living cells exposed to gamma-ray radiation. Besides in situ detection of mitochondrial fluorescence changes, we also examined the cell viability, nuclear DNA damage, reactive oxygen species (ROS), mitochondrial superoxide, citrate synthase activity, ATP, cytoplasmic and mitochondrial calcium, mitochondrial mass, mitochondrial morphology, and protein expression related to mitochondrial biogenesis, as well as the apoptosis biomarkers. As a result, we confirmed that significant mitochondrial biogenesis took place preceding the radiation-induced apoptosis, and it was closely correlated with the apoptotic cells at late stage. The involved mechanism was also discussed.

Keywords: Biochemistry methods; Biomolecular engineering; Cell biology

DOI: https://doi.org/10.1016/j.isci.2021.103038