Proteins and Protein-Complexes Underlying Mitochondrial Structure-Function and Metabolism: Implications in Diseases

Editorial

04 March 2024

Editorial: Proteins and protein-complexes underlying mitochondrial structure-function and metabolism: implications in diseases

Mohammad Golam Sabbir

Nawab John Dar

Shahnawaz Ali Bhat

Hamad H. Alanazi

and

Jeff Perry

1,106 views

0 citations

Editors

Mohammad Golam Sabbir

Nova Southeastern University

Nawab John Dar

Salk Institute for Biological Studies

Shahnawaz Ali Bhat

Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University

Jeff Perry

City of Hope National Medical Center

Impact

Review

16 November 2023

Function and regulation of ubiquitin-like SUMO system in heart

Ying Wang

, 5 more and

Nan Wang

The small ubiquitin-related modifier (SUMOylation) system is a conserved, reversible, post-translational protein modification pathway covalently attached to the lysine residues of proteins in eukaryotic cells, and SUMOylation is catalyzed by SUMO-specific activating enzyme (E1), binding enzyme (E2) and ligase (E3). Sentrin-specific proteases (SENPs) can cleave the isopeptide bond of a SUMO conjugate and catalyze the deSUMOylation reaction. SUMOylation can regulate the activity of proteins in many important cellular processes, including transcriptional regulation, cell cycle progression, signal transduction, DNA damage repair and protein stability. Biological experiments in vivo and in vitro have confirmed the key role of the SUMO conjugation/deconjugation system in energy metabolism, Ca²⁺ cycle homeostasis and protein quality control in cardiomyocytes. In this review, we summarized the research progress of the SUMO conjugation/deconjugation system and SUMOylation-mediated cardiac actions based on related studies published in recent years, and highlighted the further research areas to clarify the role of the SUMO system in the heart by using emerging technologies.

5,052 views

2 citations

Original Research

24 May 2023

Hippocampal versus cortical deletion of cholinergic receptor muscarinic 1 in mice differentially affects post-translational modifications and supramolecular assembly of respiratory chain-associated proteins, mitochondrial ultrastructure, and respiration: implications in Alzheimer’s disease

Mohammad Golam Sabbir

, 2 more and

Benedict C. Albensi

3,808 views

1 citations

Original Research

18 May 2023

Loss of cholinergic receptor muscarinic 1 impairs cortical mitochondrial structure and function: implications in Alzheimer’s disease

Mohammad Golam Sabbir

, 1 more and

Benedict C. Albensi

Introduction: Cholinergic Receptor Muscarinic 1 (CHRM1) is a G protein-coupled acetylcholine (ACh) receptor predominantly expressed in the cerebral cortex. In a retrospective postmortem brain tissues-based study, we demonstrated that severely (≥50% decrease) reduced CHRM1 proteins in the temporal cortex of Alzheimer’s patients significantly correlated with poor patient outcomes. The G protein-mediated CHRM1 signal transduction cannot sufficiently explain the mechanistic link between cortical CHRM1 loss and the appearance of hallmark Alzheimer’s pathophysiologies, particularly mitochondrial structural and functional abnormalities. Therefore, the objective of this study was to analyze the molecular, ultrastructural, and functional properties of cortical mitochondria using CHRM1 knockout (Chrm1^-/-) and wild-type mice to identify mitochondrial abnormalities.

Methods: Isolated and enriched cortical mitochondrial fractions derived from wild-type and Chrm1^-/- mice were assessed for respiratory deficits (oxygen consumption) following the addition of different substrates. The supramolecular assembly of mitochondrial oxidative phosphorylation (OXPHOS)-associated protein complexes (complex I-V) and cortical mitochondrial ultrastructure were investigated by blue native polyacrylamide gel electrophoresis and transmission electron microscopy (TEM), respectively. A cocktail of antibodies, specific to Ndufb8, Sdhb, Uqcrc2, Mtco1, and Atp5a proteins representing different subunits of complexes I-V, respectively was used to characterize different OXPHOS-associated protein complexes.

Results: Loss of Chrm1 led to a significant reduction in cortical mitochondrial respiration (oxygen consumption) concomitantly associated with reduced oligomerization of ATP synthase (complex V) and supramolecular assembly of complexes I-IV (Respirasome). Overexpression of Chrm1 in transformed cells (lacking native Chrm1) significantly increased complex V oligomerization and respirasome assembly leading to enhanced respiration. TEM analysis revealed that Chrm1 loss led to mitochondrial ultrastructural defects and alteration in the tinctorial properties of cortical neurons causing a significant increase in the abundance of dark cortical neurons (Chrm1^-/- 85% versus wild-type 2%).

Discussion: Our findings indicate a hitherto unknown effect of Chrm1 deletion in cortical neurons affecting mitochondrial function by altering multiple interdependent factors including ATP synthase oligomerization, respirasome assembly, and mitochondrial ultrastructure. The appearance of dark neurons in Chrm1^-/- cortices implies potentially enhanced glutamatergic signaling in pyramidal neurons under Chrm1 loss condition. The findings provide novel mechanistic insights into Chrm1 loss with the appearance of mitochondrial pathophysiological deficits in Alzheimer’s disease.

3,919 views

6 citations

Original Research

21 February 2023

Requirement for ER-mitochondria Ca2+ transfer, ROS production and mPTP formation in L-asparaginase-induced apoptosis of acute lymphoblastic leukemia cells

Jung Kwon Lee

, 1 more and

Ki-Young Lee

L-asparaginase causes an increase in cytoplasmic ROS level. *+pRS and *+pRS-shHAP1 cells pre-treated with XeC, RuR, CsA or Mito-Tempo then treated with L-asparaginase were stained with DCFDA and examined by microscopy. Cell images were acquired using an Olympus 1 × 71 inverted microscope at ×160 magnification. The bar graph shows mean fluorescence intensity of captured images measured using the ImageJ software with values from cells stimulated with L-asparaginase normalized to 1. Values are means ± SEM from three independent experiments (n = 3). **p < 0.05.

Acute lymphoblastic leukemia (aLL) is a malignant cancer in the blood and bone marrow characterized by rapid expansion of lymphoblasts. It is a common pediatric cancer and the principal basis of cancer death in children. Previously, we reported that L-asparaginase, a key component of acute lymphoblastic leukemia chemotherapy, causes IP3R-mediated ER Ca²⁺ release, which contributes to a fatal rise in [Ca²⁺]_cyt, eliciting aLL cell apoptosis via upregulation of the Ca²⁺-regulated caspase pathway (Blood, 133, 2222–2232). However, the cellular events leading to the rise in [Ca²⁺]_cyt following L-asparaginase-induced ER Ca²⁺ release remain obscure. Here, we show that in acute lymphoblastic leukemia cells, L-asparaginase causes mitochondrial permeability transition pore (mPTP) formation that is dependent on IP3R-mediated ER Ca²⁺ release. This is substantiated by the lack of L-asparaginase-induced ER Ca²⁺ release and loss of mitochondrial permeability transition pore formation in cells depleted of HAP1, a key component of the functional IP3R/HAP1/Htt ER Ca²⁺ channel. L-asparaginase induces ER Ca²⁺ transfer into mitochondria, which evokes an increase in reactive oxygen species (ROS) level. L-asparaginase-induced rise in mitochondrial Ca²⁺ and reactive oxygen species production cause mitochondrial permeability transition pore formation that then leads to an increase in [Ca²⁺]_cyt. Such rise in [Ca²⁺]_cyt is inhibited by Ruthenium red (RuR), an inhibitor of the mitochondrial calcium uniporter (MCU) that is required for mitochondrial Ca²⁺ uptake, and cyclosporine A (CsA), an mitochondrial permeability transition pore inhibitor. Blocking ER-mitochondria Ca²⁺ transfer, mitochondrial ROS production, and/or mitochondrial permeability transition pore formation inhibit L-asparaginase-induced apoptosis. Taken together, these findings fill in the gaps in our understanding of the Ca²⁺-mediated mechanisms behind L-asparaginase-induced apoptosis in acute lymphoblastic leukemia cells.