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Cristae – The Powerhouses Within
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Cristae – The Powerhouses Within

Mitochondria are dynamic organelles that constantly change their shapes and sizes. The shaping of mitochondria affects the functions of the mitochondrial supercomplexes that are located within the folds of the cristae (inner mitochondrial membrane).  The relationship between cristae and the respiratory complexes ultimately determines energy production by mitochondria and bioenergetic capacity of cells. One can say the health of an organism depends on the ability of its mitochondria to change its shape.

Mitochondria dysfunction is believed to be a major contributor in the aging process as a result of decreased energy production or increased oxidative stress due to excess electron leakage in the electron transport chain (ETC).  It is believed that destabilization of the supercomplexes may be a primary reason for the development of mitochondrial aging phenotypes [1]. 

Since the introduction of the concept of supercomplex by Schägger et al. in 2000 [2], extensive studies have been performed to unravel the reasons for the formation of supercomplex organization in OXPHOS (oxidative phosphorylation).  It is now widely accepted that the stability and efficiency of mitochondrial respiratory protein Complex I can be significantly enhanced by the formation of supercomplexes with Complex III and IV, and that stability of Complex I is strongly decreased when it is not assembled in the respirasome (another name for supercomplex) [3].  

In many organisms, complex II do not appear to form part of supercomplexes. Complex II of the electron transport chain is not involved in proton pumping [4], but Complex II, or succinate dehydrogenase, can transfer electrons from succinate to ubiquinone, and therefore connect the Krebs (citric acid) cycle to the respiratory chain.  Due to this unique feature, Complex II are seldom seen to form part of any respiratory chain supercomplexes [5]. Yet Complex II have been observed to be very mobile, showing high abundance in close proximity to the cristae junction, especially during remodeling processes [6].   

Megacomplexes Enhance Electron Transfers

The question whether all four electron transport chain respiratory complexes are involved in the formation of supercomplexes have been questioned ever since the discovery of supercomplexes.  Due to certain limitations in current structural biology and biochemical techniques, this question has not been answered with any degree of certainty nor satisfaction [7]. 

In 2017, Guo et al. for the first time using medium resolution structure of mitochondria from cultured human cells, accurately identified all of the 45 subunits in each complex I, 22 subunits in complex III, 13 subunits in each complex IV, and the 2 cytochrome c molecules [8]. 

The discovery of the existence of megacomplexes supports the theory of the circular model where the organization of the respiratory chain complexes fits tightly with the structure of the cristae surface.  Guo et al. also observed a mass of unoccupied area between complex I and complex IV, which could very well be occupied by complex II [8]. A recent analysis of bovine heart mitochondrial was able to demonstrate that pharmacological inhibition of complex I and II can cause the dissociation of supercomplexes, however, complex II has NO EFFECT on the assembly of supercomplexes [25]. 

[Source:Guo et al., 2017, Cell 170, 1247–1257 September 7, 2017 ª 2017 Elsevier Inc. http://dx.doi.org/10.1016/j.cell.2017.07.050]

 

The Single Site Model of Electron Transfer Pathways in Mitochondria

The identification of the exact placement of the various subunits in megacomplexes also led to the proposal of a more efficient electron transfer pathway that could replace the classic Q cycle model proposed by Mitchell in 1975 [9]. If you look at the diagrams below, the Q cycle model shows electrons being transferred in a rather circuitous route (arrows indicate electron transfer pathways).  The ‘single site model’ proposed by Guo et al. allows for the highest energy conversion efficiency based on structural analyses [10]. In this model, not only binding sites are closer in proximity, both electrons of ubiquinol are utilized, while the polar head of the ubiquinone molecule does not have to cross hydrophobic membranes [11]. 

[Source: Biomedical Journal Volume 41, Issue 1, February 2018, Pages 9-20 Runyu Guo et al. Structure and mechanism of mitochondrial electron transport chain]


There is no question that the formation and assembly of supercomplexes are essential to proper mitochondrial function. The pathogenesis of many diseases including neurodegeneration [12], heart failure [13], and even aging [15] are dependent upon the assembly of supercomplexes, and not the actual amount of individual complexes that are affected.  

In a canine model of heart failure, defects in oxidative phosphorylation was identified within the electron transport chain of heart mitochondria. However, the activities of the individual complexes were actually normal.  There was, however, a decrease in the amount of supercomplexes formed between complexes I, III and IV, showing that defective ETC was caused by failure to form supercomplexes, rather than individual component malfunctions [16]. 

Supercomplexes and megacomplexes are localized at the cristae, thus, the formation and assembly of supercomplexes are directly regulated by the shaping and remodeling of cristae.

Cristae Morphology & Mitochondrial Bioenergetics

Under stressful cellular conditions such as nutrient deprivation or hypoxia, mitochondria and cristae will change shapes to adapt to changing energy (ATP) requirements.  The remodeling of mitochondrial cristae structure is a critical part of the survival response mechanisms designed by Nature in order to meet changing energy demands during stress or growth and development of the organism [17]. 

As early as 1966, dynamic changes in cristae structures were reported by Hackenbrock, who observed two reversible conformations in the cristae of mouse liver mitochondria. In the ‘condensed’ state, mitochondria had dense, compacted matrix with enlarged cristae, while mitochondria in the ‘orthodox’ states exhibited a matrix that is less dense with cristae that were compacted [18].  

[Source: Biochimica et Biophysica Acta 1763 (2006) 542–548 Carmen A. Mannella  Review Structure and dynamics of the mitochondrial inner membrane cristae]

 

Mitochondria have two lipid membrane layers. The outer membrane is similar to plasma membranes, while the inner layer can be classified into the boundary type that runs in close proximity to the outer membrane, and that of the cristae, which have extended intermembrane spaces and are connected to the boundary membrane via tubular structures called crista junctions [17]. 

Outer & Innermembranes,  Cristae of Intact Rat Liver Mitochondrion (700 nm) by Cryo-electron Tomography 

[Source: Biochimica et Biophysica Acta 1763 (2006) 542–548 Carmen A. Mannella  Review Structure and dynamics of the mitochondrial inner membrane cristae]

 

Cristae junctions separate cristae from inner boundary membranes and serve as regulators for the distribution of proteins, effectively partitioning the metabolite content of intracristal and intermembrane spaces.  This important aspect highly influences OXPHOS functions as well as apoptotic events where cristae junctions modulate the release of cytochrome C from instracristal space into the cytosol [19].

[Source: Biochimica et Biophysica Acta (BBA) – Bioenergetics Volume 1857, Issue 8, August 2016, Pages 1167-1182 JavierGarcía-Bermúdez, José M.Cuezva The ATPase Inhibitory Factor 1 (IF1): A master regulator of energy metabolism and of cell survival]

 

Whether cristae junctions are kept in an open or closed state is dependent upon a protein called Optic Atrophy 1 or OPA1. 

OPA1 Regulates Cristae Remodeling

Optic atrophy 1 (OPA1) is a dynamin-like protein, which are membrane-active proteins that are actively involved in membrane dynamics, with the ability to trigger vesicle formation, membrane fusion or organelle division in eukaryotic cells [20].

The recent investigation into how OPA1 mutations cause mitochondrial defects linked to neurodegenerative symptoms in patients suffering from optic atrophy and Parkinson’s revealed the importance of OPA1 in mitochondrial bioenergetics [28].  Mutations in OPA1 has been associated with Parkinsonism and cognitive decline, where loss of OPA1 functions compromise dopaminergic cell viability [21]. 

OPA1 is now accepted to be a bifunctional protein that can both promote mitochondrial fusion, and also regulate apoptosis by controlling cristae remodeling as well as cytochrome c redistribution [22].  OPA1 is able to inhibit cytochrome c release, reduce mitochondrial dysfunction and cell death initiated by intrinsic stimuli such as cellular stress. OPA1 can dynamically regulate the shape of cristae, which is required to maintain mitochondrial activity under low-energy environments. Lack of energy substrates can induce OPA1 oligomerization which will narrow cristae junctions [23]. 

Mitochondria have been observed to increase their length and the number of cristae during nutrient starvation. During starvation induced autophagy, increased cristae in elongated mitochondria have increased dimerization and activity of ATP synthase, therefore are spared from autophagic degradation because these mitochondria with increased cristae can maintain adequate ATP production.  Whereas when the process of mitochondria/cristae remodeling is pharmacologically blocked, mitochondria would actually CONSUME ATP, that would initiate starvation-induced cell death [24].

[Source: Biomedical Journal Volume 41, Issue 1, February 2018, Pages 9-20 Runyu Guo et al. Structure and mechanism of mitochondrial electron transport chain]

 

The remodeling of mitochondria and cristae under stressful conditions help regulate mitochondrial efficiency by increasing supercomplex assembly of the various ETC respiratory complexes, increasing the capacity for ATP production.  Ultimately, mitochondrial and cristae structure dictates the bioenergetic status of cells, allowing sustained ATP production that will support the survival of cells with high energy demands [23].

Under nutrient stress created by glucose deprivation, mitochondria cristae repond by increasing the formation of electron transfer chain supercomplexes.  Limited glucose supply forces cells to use mitochondrial OXPHOS to maintain cellular energy supply. Mitochondria increase cristae density and the formation of increased supercomplexes that are housed by these cristae, ultimately increasing ATP energy supply. During these processes, mitochondria reorganize the various respiratory complexes in combination with the expansion of mitochondria cristae.  Overexpression of OPA1 under these nutrient deprivation conditions significantly enhanced cristae density and supercomplex levels [26]. 

Even a slight elevation in the levels of OPA1 in normal cells can promote cristae tightness and increase the activity and efficiency of ETC proteins [17].  Whereas the loss of OPA1 has been shown to disrupt the shape of cristae, which leads to severe perturbation in supercomplex assembly and energy production capacity [17, 23].  It appears that the disruption of supercomplex formation in the absence of OPA1 precedes both the impairment of mtDNA copy number and the release of apoptotic death signals [17]. 

The landmark discovery released in October 2019 by Wolf et al. truly elevated the importance of cristae as independent powerhouses within mitochondria .

Cristae Are The True Powerhouses Within

Wolf et al. introduced to the world a distinct new model where cristae within the same mitochondria behave as independent bioenergetic units that maintain different mitochondrial membrane potential (ΔΨm) [29].  This discovery is truly significant in our high tech world that is besieged by electromagnetic radiation. Long-term exposure to electromagnetic frequencies of 900 and 1800 MHz used by mobile phones can cause deleterious depolarization of mitochondrial membranes, leading to mitochondrial oxidative stress, apoptosis and calcium ion influx [30].  

The mitochondrial membrane potential (ΔΨm) is the main source of chemical energy that is responsible for driving proton re-entry from the intermembrane space through the ATP synthase back into the mitochondrial matrix [31].  The maintenance of appropriate ΔΨm is critical for mitochondrial energy production as the energy available for ATP synthesis is directly derived from mitochondrial membrane potential (ΔΨm). Depolarization translates into decreased energy available for ATP synthesis. 

In order to maintain a high mitochondrial membrane potential (ΔΨm), the ΔΨ of the cristae membrane must be more negative compared to its neighboring inner boundary membrane, otherwise, protons would not be able to remain in the cristae lumen. The inner mitochondrial membrane (IMM), consisting of cristae and inner boundary membranes (IBM), has long been considered to carry a uniform ΔΨm, and that mitochondria is a single bioenergetic unit.  Nothing can be further from the truth!

Previous experiments that would demonstrate the complete collapse of the mitochondrial membrane potential (ΔΨm) through depolarization depended upon the use of microscopes that allowed for single mitochondrion and not single crista resolution. The time lapse was also at extended lengths of 5-second intervals [32]. 

Wolf et al. showed that following laser-induced depolarization at  0.30, 0.45, and 0.60 seconds, mitochondrion lost ΔΨm in the areas closest to the site of laser stress first. As time elapsed, by about 2.1 seconds, the entire mitochodnrion lost all of its ΔΨm.  

Further quantification showed that following depolarization, mitochondria remained more polarized at sites that were distant from targeted laser stress compared to the sites close to laser induced stress. 

Using high or super-resolution imaging showed cristae are actually individual but interconnected batteries within mitochondria.  This experiment demonstrated that the ΔΨm is actually not homogeneous along the inner mitochondrial membrane, but showed significant differences between cristae.  The authors were able to observe that during transient depolarization, some cristae can maintain polarity despite the collapse of ΔΨm in adjacent cristae.  

 

Mitochondrion showing heterogeneity of ΔΨm

[Source: EMBO J (2019)38:e101056 Dane M Wolf et al. Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent | The EMBO Journal]

 

The capacity of cristae to maintain different membrane potential is dependent upon the electrical insulation regulated by cristae junctions. Both the increase and decrease in membrane potential supports different metabolic functions such as ATP production or ROS signaling. It is interesting to speculate that cristae within the same mitochondrion can actually carry out different functions of either ATP production or ROS signaling.  Not to mention the compartmentalization of ΔΨm in cristae are important failsafe mechanisms that can limit the impact of localized damage [29]. 

With this groundbreaking discovery, it is becoming very clear that the role of cristae morphology has deep implications for human health as perturbations in cristae structure are associated with a wide array of pathologies.  In a world where living organisms are constantly bombarded by electromagnetic radiation, the role of vitamin C, ascorbic acid in the maintenance of cristae bioenergetics and mitochondrial dynamics cannot be understated ….….  To Be Continued  ……..

 

References

[1] Age-related decline in mitochondrial bioenergetics: Does supercomplex destabilization determine lower oxidative capacity and higher superoxide production?  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096948/ 

[2] Supercomplexes in the respiratory chains of yeast and mammalian mitochondria https://www.ncbi.nlm.nih.gov/pmc/articles/PMC302020/ 

[3] Supramolecular Organization of Respiratory Complexes | Annual Review of Physiology  https://www.annualreviews.org/doi/10.1146/annurev-physiol-021115-105031

[4] The Respiratory Chain Consists of Four Complexes: Three Proton Pumps and a Physical Link to the Citric Acid Cycle – Biochemistry – NCBI Bookshelf https://www.ncbi.nlm.nih.gov/books/NBK22505/

[5] The higher level of organization of the oxidative phosphorylation system: mitochondrial supercomplexes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780661/

[6] Functional role of mitochondrial respiratory supercomplexes – ScienceDirect https://www.sciencedirect.com/science/article/pii/S0005272813001874 

[7]  Current Challenges in Elucidating Respiratory Supercomplexes in Mitochondria: Methodological Obstacles | Physiology https://www.frontiersin.org/articles/10.3389/fphys.2018.00238/full#B9

[8] Architecture of Human Mitochondrial Respiratory Megacomplex I2III2IV2 https://www.cell.com/cell/fulltext/S0092-8674(17)30887-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867417308875%3Fshowall%3Dtrue 

[9] Protonmotive redox mechanism of the cytochrome b-c1 complex in the respiratory chain: protonmotive ubiquinone cycle. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/239860

[10] Amazing structure of respirasome: unveiling the secrets of cell respiration https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5205662/

[11] Structure and mechanism of mitochondrial electron transport chain – ScienceDirect https://www.sciencedirect.com/science/article/pii/S2319417017303025#bib9

[12] Mitochondrial Complex I Activity is Conditioned by Supercomplex I-III2-IV Assembly in Brain Cells: Relevance for Parkinson’s Disease. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/28197854

[13] Cardiac metabolic pathways affected in the mouse model of barth syndrome. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/26030409

[14] Supercomplexes of the mitochondrial electron transport chain decline in the aging rat heart. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/19679098

[15] Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/18710878

[16] Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/18710878

[17] Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency – ScienceDirect https://www.sciencedirect.com/science/article/pii/S009286741301026X

[18] Ultrastructural bases for metabolically linked mechanical activity in mitochondria. I. Reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/5968972/

[19] Mic10 Oligomerization Pinches off Mitochondrial Cristae https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431669/

[20] Dynamin-Like Proteins Are Potentially Involved in Membrane Dynamics within Chloroplasts and Cyanobacteria https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827413/

[21] Syndromic parkinsonism and dementia associated with OPA 1 missense mutations https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008165/

[22] Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/12509422

[23] OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/25298396 

[24] During autophagy mitochondria elongate, are spared from degradation and sustain cell viability https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088644/ 

[25] Elucidating the contribution of ETC complexes I and II to the respirasome formation in cardiac mitochondria | Scientific Reports https://www.nature.com/articles/s41598-018-36040-9 

[26] ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis: Molecular Cell https://www.ncbi.nlm.nih.gov/pubmed/31023583 

[27] Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent | The EMBO Journal https://www.embopress.org/doi/full/10.15252/embj.2018101056

[28] Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032926/

[29]  Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent | The EMBO Journal https://www.embopress.org/doi/full/10.15252/embj.2018101056

[30] Long term exposure to cell phone frequencies (900 and 1800 MHz) induces apoptosis, mitochondrial oxidative stress and TRPV1 channel activation in t… – PubMed – NCBI  https://www.ncbi.nlm.nih.gov/pubmed/29332300

[31] Coupling of Phosphorylation to Electron and Hydrogen Transfer by a Chemi-Osmotic type of Mechanism | Nature https://www.nature.com/articles/191144a0

[32] Mitochondrial filaments and clusters as intracellular power-transmitting cables. – PubMed – NCBI https://www.ncbi.nlm.nih.gov/pubmed/11165513?dopt=Abstract

 

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Doris Loh

Doris Loh

Doris Loh is an independent researcher and writer specializing in the investigation of familiar and innovative health topics using unique perspectives in traditional and quantum biology. Her training as a classical pianist allows her the freedom to explore concepts and theories with a curiosity that often results in distinctive conclusions. Recent works by Doris are focused on how health and disease are greatly affected by electromagnetic radiation that surround us everywhere we go. Her works on EMF offer insight and solutions to the challenges humans and other living organisms face during this era of change. Major works by Doris include an in-depth series on deuterium, as well as a startling series on the birefringent quantum properties of the major REDOX balancer, Vitamin C (ascorbic acid). The ongoing series on COVID-19 is recognized around the world for the in-depth coverage of the disease and discussion on holistic alternatives for prevention and treatment.

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