ReviewDynamic of mitochondrial network, cristae, and mitochondrial nucleoids in pancreatic β-cells
Introduction
Pancreatic islets (PI) and notably β-cells represent the endocrine pancreas, a center of regulation of glucose homeostasis for the organism. Numerous physiological and pathological aspects are still unknown, such as a time course of their biogenesis, existence of de novo differentiation of stem cells into β-cells in adult organism, as well as the initial events leading to a vicious spiral of type 2 diabetes development (Ježek et al., 2019a). Indeed the type 2 diabetes becomes a world-wide epidemic disease. Its etiology comprises not only the peripheral insulin resistance, i.e., impaired response to insulin of tissues like skeletal muscle, white adipose tissue, or liver, but involves also the dysfunction of β-cells. Progress in the β-cell pathology during the type 2 diabetes development proceeds in numerous steps. This begins by prediabetic states and extends to the increasing β-cell dysfunction and decreasing number of β-cells, notably by their dedifferentiation and transdifferentiation. Initial events include compensation responses of β-cells, their reversal upon progression and the accompanied low-grade PI inflammation (Ježek et al., 2019a). Mutual interaction of factors secreted or located on the surface of deterioriated β-cells with immune system and peripheral organs leads to the peripheral insulin resistance. In later stages of type 2 diabetes the key aspects accelerate to develop pathological states even more. These aspects include profound oxidative stress, lipotoxicity and glucotoxicity, all affecting β-cells.
Since the canonical mechanism of glucose-stimulated insulin secretion (GSIS) is based on the increased oxidative phosphorylation in the β-cell mitochondrion, its dysfunction and impairment of the physiological regulations involved leads to type 2 diabetes. When any mechanisms of energy production, metabolic regulations, and information signaling relevant to the mitochondrial physiology are disturbed, resulting dysfunction abolishes GSIS. Hence not only insults having the direct effects, but also those having the indirect effect become transferred to the progressive development of type 2 diabetes. Direct insults inhibit the oxidative phosphorylation, while the indirect effects are related to proteins shaping mitochondrial morphology and proper biogenesis/degradation balance. All these essential functions must be intact in the mitochondrion, otherwise a pathological state is developed.
Physiologically, ATP elevation leads to the closure of the plasma mebrane ATP-sensitive K+ channel, inducing the calcium influx to the cell cytosol in concert with other channels. This finally triggers exocytosis of insulin granules. All these processes are subjected to delicate regulations. Insulin exocytosis is also induced by numerous other mechanisms, which is out scope of this review (but see Ježek et al., 2019a). Nevertheless, any pathological state is likely to be reflected by the altered mitochondrial network morphology and altered cristae ultramorphology. In addition, concomitant impaired biogenesis of mitochondrion, mutations of mitochondrial DNA (mtDNA), and impairment of mtDNA gene expression and maintenance machinery leads also to the pathological changes of the entities termed nucleoids (Ježek et al., 2019b). Nucleoids are nucleoprotein complexes representing discrete and multiple (~1000 per cell) sites of mtDNA locations.
In this review, we attempted to briefly describe the knowledge on pathological relations of the mitochondrial network, mitochondrial cristae and nucleoid morphology. Morphological alternations may be either causes or consequences of the type 2 diabetes pathology. For each morphology level, we provide first a brief review of factors determining the physiologically normal morphology. When possible, details are explained using the available reports on pancreatic β-cells. Next, we describe possible changes, in order to understand the observed pathological changes. In this way, we summarize the available literature concerning mitochondrial morphology of pancreatic β-cells in relation to normal and diabetic states. Despite the fact that a morphological diagnostics would be plausible only for PI intended for transplantation, the knowledge of morphological alternations is very important, since they reflect the key pathological changes in pancreatic β-cells.
Section snippets
β-Cell mitochondrion
Mitochondrion is indeed the most appropriate term for the organelle representing the bioenergetics, metabolic, and informational regulatory center of the cell. Plural, i.e. “mitochondria”, has been historically derived from inspections of transmission electron microscopy (TEM) sections of the mitochondrial network, such as in the pioneer work of Palade (1964). The term “mitochondria” naturally corresponds to the artificially cut mitochondrial network upon the typical isolation of the organelle.
Compartments of mitochondrion
The complex structure of the IMM comprises the two major parts (Fig. 5A): i) the inner boundary membrane (IBM), which is parallel to OMM, thus being nearly cylindrical in tubules; and, ii) mitochondrial cristae, representing long protrusions (Kukat et al., 2015; Sun et al., 2007) with rather sharp edges at metabolic rich conditions (Fig. 5A; see Section 3.4). Cristae are often perpendicular to OMM (Pernas and Scorrano, 2016; Plecitá-Hlavatá and Ježek, 2016). Such canonical IMM morphology
Nucleoids of mtDNA
An autonomous robust genome is present in the mitochondrion. Its influence on cell physiology and pathology is much higher than would be judged from its small size. Mitochondrial DNA is intron-free. Its expression proceeds through its own genetic code. mtDNA is circular double-stranded molecule, highly packed with a density found typically in prokaryotes (Gustafsson et al., 2016). The robustness of the mtDNA genome is given by the presence of mtDNA in multiple copies in a single cell, typically
Future perspectives
Understanding of a self-identity checking for pancreatic β-cells, their information signaling to the periphery, notably during the low-grade inflammation of pancreatic islets, and knowledge of other molecular events during the progressive type 2 diabetes development are required to understand the etiology of this disease and design novel ways to cure it. The concomitant understanding of mitochondrial pathology is an integral part of these efforts. In order to proceed in deeper insight, the use
Declaration of Competing Interest
Both authors have no competing interests to declare.
Acknowledgements
This work was supported by the Grant Agency of the Czech Republic grant number 17-08565S and 17-01813S.
References (129)
- et al.
Assessment of mitochondrial DNA as an indicator of islet quality: an example in Goto Kakizaki rats
Transplant. Proc.
(2011) - et al.
Mic10 Oligomerizes to bend mitochondrial inner membranes at cristae junctions
Cell Metab.
(2015) Mitochondrial dynamics in aging and disease
Prog. Mol. Biol. Transl. Sci.
(2014)- et al.
Visualizing superoxide production in normal and diabetic rat islets of Langerhans
J. Biol. Chem.
(2003) - et al.
The layered structure of human mitochondrial DNA nucleoids
J. Biol. Chem.
(2008) - et al.
Central role of Mic10 in the mitochondrial contact site and cristae organizing system
Cell Metab.
(2015) - et al.
Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling
Cell
(2006) - et al.
4Pi microscopy reveals an impaired three-dimensional mitochondrial network of pancreatic islet beta-cells, an experimental model of type-2 diabetes
Biochim. Biophys. Acta
(2010) - et al.
3D super-resolution microscopy reflects mitochondrial cristae alternations and mtDNA nucleoid size and distribution
Biochim. Biophys. Acta Bioenerg.
(2018) - et al.
OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion
Cell
(2006)
PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression
Cell Metab.
Structural basis of mitochondrial transcription initiation
Cell
Zen and the art of mitochondrial DNA maintenance
Trends Genet.
Mammalian mitochondrial nucleoids: organizing an independently minded genome
Mitochondrion
Mitochondrial nucleoids: superresolution microscopy analysis
Int. J. Biochem. Cell Biol.
Mitochondria: from cell death executioners to regulators of cell differentiation
Trends Cell Biol.
POLB: a new role of DNA polymerase beta in mitochondrial base excision repair
DNA Repair (Amst)
Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release
Mol. Asp. Med.
Fatty acids suppress autophagic turnover in β-cells
J. Biol. Chem.
Profile of cardiac lipid metabolism in STZ-induced diabetic mice
Lipids Health Dis.
Dynamin-related protein 1 at the crossroads of cancer
Genes (Basel)
Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease
Mol. Cell
The relevance of mitochondrial membrane topology to mitochondrial function
Biochim. Biophys. Acta Mol. basis Dis.
Prevention by metformin of alterations induced by chronic exposure to high glucose in human islet beta cells is associated with preserved ATP/ADP ratio
Diabetes Res. Clin. Pract.
Mitochondria control acute and chronic responses to hypoxia
Exp. Cell Res.
Dynamin-related protein 1 mediates high glucose induced pancreatic beta cell apoptosis
Int. J. Biochem. Cell Biol.
Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome
Cell Metab.
Transcribing β-cell mitochondria in health and disease
Mol. Metab.
Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells
Mol. Metab.
Expedited approaches to whole cell electron tomography and organelle mark-up in situ in high-pressure frozen pancreatic islets
J. Struct. Biol.
Mitochondrial ribosomal protein L12 is required for POLRMT stability and exists as two forms generated by alternative proteolysis during import
J. Biol. Chem.
Mitophagy and quality control mechanisms in mitochondrial maintenance
Curr. Biol.
Integration of superoxide formation and cristae morphology for mitochondrial redox signaling
Int. J. Biochem. Cell Biol.
Mitochondrial oxidative phosphorylation and energetic status are reflected by morphology of mitochondrial network in INS-1E and HEP-G2 cells viewed by 4Pi microscopy
Biochim. Biophys. Acta
Mic10, a core subunit of the mitochondrial contact site and cristae organizing system, interacts with the dimeric F 1 F o -ATP synthase
J. Mol. Biol.
Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells
Biochem. Biophys. Res. Commun.
Human mitochondrial DNA is packaged with TFAM
Nucleic Acids Res.
Delta cell hyperplasia in adult Goto-Kakizaki (GK/MolTac) diabetic rats
J. Diabetes Res.
Delaunay algorithm and principal component analysis for 3D visualization of mitochondrial DNA nucleoids by biplane FPALM/dSTORM
Eur. Biophys. J.
Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients
Diabetologia
Mitochondrial network regulation and its potential interference with inflammatory signals in pancreatic beta cells
Diabetologia
ATAD3 proteins: brokers of a mitochondria-endoplasmic reticulum connection in mammalian cells
Biol. Rev.
Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria
Microsc. Res. Tech.
Role of mitochondrial inner membrane organizing system in protein biogenesis of the mitochondrial outer membrane
Mol. Biol. Cell
Superresolution fluorescence imaging of mitochondrial nucleoids reveals their spatial range, limits, and membrane interaction
Mol. Cell. Biol.
Modulation of autophagy influences the function and survival of human pancreatic beta cells under endoplasmic reticulum stress conditions and in type 2 diabetes
Front. Endocrinol. (Lausanne)
Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity?
Philos. Trans. R. Soc. B
Recent insights into the structure and function of Mitofusins in mitochondrial fusion
F1000Research
A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes
Nat. Genet.
Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for beta cell function
Diabetologia
Cited by (23)
Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes
2023, Biochimica et Biophysica Acta - BioenergeticsCitation Excerpt :In addition to swelling, we found altered spreading of IMM-compounds after mitochondrial fusion. Mitochondrial dynamics plays a crucial role for OXPHOS organization [37,63,96] and cristae dynamics [5,36,68,97–100]. Until now, no data have been available on IMM dynamics in cardiac cells.
Mitochondrial defects in pancreatic beta-cell dysfunction and neurodegenerative diseases: Pathogenesis and therapeutic applications
2023, Life SciencesCitation Excerpt :The pyruvate product was converted to acetyl-CoA by an enzyme called pyruvate dehydrogenase complex, which was then transported into mitochondria, where ATP was created by the TCA cycle and OXPHOS to up-regulate the cytosolic ATP concentration [39]. This result balances the ATP-sensitive K+ channel's lockdown effect against the voltage-dependent Ca2+ on the plasma membrane in order to allow more Ca2+ to pass into the cytosolic area, resulting in insulin exocytosis [36,37]. ROS are a category of reactive chemicals formed from molecular oxygen that include superoxide anion (O2−), hydroxyl radical (OH), and hydrogen peroxide as by-products of biological metabolism (H2O2) ROS are tightly controlled in cells by antioxidant defense mechanisms that include superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), ascorbic acid (vitamin C), tocopherol (vitamin E), and glutathione (GSH).
Mitochondrial calcium in command of juggling myriads of cellular functions
2021, MitochondrionCitation Excerpt :Similar to in vitro studies, in vivo studies using beta cell-MCU knockout mice also had shown the impairment of insulin secretion along with the reduction in the mitochondrial calcium levels (Ghosh et al., 2020). Type 2 diabetes progression stems from dysfunction of β-cells caused due to imbalance in mitochondrial calcium (Ježek and Dlasková, 2019). Similar to the potentiation of insulin secretion, aldosterone secretion is also increased by increased mitochondrial calcium (Wiederkehr et al., 2011).
Mitochondrial superoxide/hydrogen peroxide: An emerging therapeutic target for metabolic diseases
2020, Free Radical Biology and MedicineCitation Excerpt :Furthermore, hyperglycemia-stimulated mitochondrial •O2− generation in turn promotes PKC activation, AGEs formation and the increase of hexosamine pathway flux via activating DNA strand break-mediated poly(ADP-ribose) polymerase and GAPDH poly(ADP-ribosyl)ation [58]. Mitochondria, as glucose sensor and signaling center, are damaged to varying degrees at different stages of diabetes [59]. Sustained hyperglycemia pressure-induced inflammation is one of the hallmarks of T2D [60].
Mitochondrial Dynamics in Signaling and Disease
2019, MitochondrionThe potential of therapeutic strategies targeting mitochondrial biogenesis for the treatment of insulin resistance and type 2 diabetes mellitus
2024, Archives of Pharmacal Research