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Calcium Overload and Mitochondrial Metabolism

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Walkon, Lauren L., Strubbe-Rivera, Jasiel O., Bazil, Jason N.·2022·Biomolecules
DOI 10.3390/biom12121891PMC PMC9775684
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Abstract

Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming the mitochondrial calcium retention capacity leads to loss of mitochondrial function. In moderate amounts, however, ATP synthesis rates are inhibited in a calcium-titratable manner. While the consequences of extreme calcium overload are well-known, the effects on mitochondrial function in the moderately loaded range remain enigmatic. These observations are associated with changes in the mitochondria ultrastructure and cristae network. The present mini review/perspective follows up on previous studies using well-established cryo–electron microscopy and poses an explanation for the observable depressed ATP synthesis rates in mitochondria during calcium-overloaded states. The results presented herein suggest that the inhibition of oxidative phosphorylation is not caused by a direct decoupling of energy metabolism via the opening of a calcium-sensitive, proteinaceous pore but rather a separate but related calcium-dependent phenomenon. Such inhibition during calcium-overloaded states points towards mitochondrial ultrastructural modifications, enzyme activity changes, or an interplay between both events.

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Crossref · 10.3390/biom12121891

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Figures

Figure 1 Calcium overload. In low amounts, calcium enhances mitochondrial function by activating several Ca2+–sensitive catabolic enzymes. In moderate amounts, depressed rates of oxidative phosphorylation become observable. In extreme amounts, mitochondria become structurally compromised and consume ATP in a futile attempt to restore homeostasis.
Figure 1 Calcium overload. In low amounts, calcium enhances mitochondrial function by activating several Ca2+–sensitive catabolic enzymes. In moderate amounts, depressed rates of oxidative phosphorylation become observable. In extreme amounts, mitochondria become structurally compromised and consume ATP in a futile attempt to restore homeostasis.CC BY · PubMed Central
Figure 2 Mitochondrial ultrastructural changes associated with calcium overload. From left to right, IMOD [16] 3D mitochondrial reconstructions from cryo–electron tomography data where mitochondria were exposed to zero Ca2+, a bolus of 25 µM CaCl2, a bolus of 50 µM CaCl2 [2], and 1µM CsA. Calcium causes a decrease in cristae volume in a titratable manner. CsA leads to an expanded cristae volume and altered outer membrane morphology.
Figure 2 Mitochondrial ultrastructural changes associated with calcium overload. From left to right, IMOD [16] 3D mitochondrial reconstructions from cryo–electron tomography data where mitochondria were exposed to zero Ca2+, a bolus of 25 µM CaCl2, a bolus of 50 µM CaCl2 [2], and 1µM CsA. Calcium causes a decrease in cristae volume in a titratable manner. CsA leads to an expanded cristae volume and altered outer membrane morphology.CC BY · PubMed Central
Figure 3 Method used to calculate the duration of oxidative phosphorylation. The transition is marked with an open circle and a shaded area for each condition that was used to estimate the point the majority of the O2 flux switches from oxphos using the original ADP bolus to futile ATP cycling. This ATP cycling occurs when the rate of mitochondrial ATP efflux matches the ATP hydrolysis rate from extramitochondrial ATPase contaminants. All mitochondrial preparations when Mg2+ is present contain these contaminants. The arrows point to the start and end of oxphos for each condition.
Figure 3 Method used to calculate the duration of oxidative phosphorylation. The transition is marked with an open circle and a shaded area for each condition that was used to estimate the point the majority of the O2 flux switches from oxphos using the original ADP bolus to futile ATP cycling. This ATP cycling occurs when the rate of mitochondrial ATP efflux matches the ATP hydrolysis rate from extramitochondrial ATPase contaminants. All mitochondrial preparations when Mg2+ is present contain these contaminants. The arrows point to the start and end of oxphos for each condition.CC BY · PubMed Central
Figure 4 Analysis of O2 cost for each experimental condition. (A) Observed ADP consumed (ATP produced) per O2 across a range of calcium loads with and without CsA. (B) Estimated ATP/O2 ratios across a range of calcium loads with and without CsA. The theoretical PO2 value for NADH linked substrates is approximately 5.46 assuming 8/3 + 1 H+ per ATP generated and exported and 20 H+ per O2 consumed. (C) Calculated mean O2 waste during the oxphos period used to correct apparent ADP per O2 data shown in panel A to estimate the PO2 values shown in panel B. (D) Calculated excess O2 cost plotted against oxphos duration from panel C. (E) Oxphos duration estimated from data for each condition. Color key: blue, EGTA; orange, 40 nmol/mg, yellow, 250 nmol/mg, and 500 nmol/mg Ca2+ condition. Data are presented as the mean ± standard deviation for a sample size of n ≥ 8.
Figure 4 Analysis of O2 cost for each experimental condition. (A) Observed ADP consumed (ATP produced) per O2 across a range of calcium loads with and without CsA. (B) Estimated ATP/O2 ratios across a range of calcium loads with and without CsA. The theoretical PO2 value for NADH linked substrates is approximately 5.46 assuming 8/3 + 1 H+ per ATP generated and exported and 20 H+ per O2 consumed. (C) Calculated mean O2 waste during the oxphos period used to correct apparent ADP per O2 data shown in panel A to estimate the PO2 values shown in panel B. (D) Calculated excess O2 cost plotted against oxphos duration from panel C. (E) Oxphos duration estimated from data for each condition. Color key: blue, EGTA; orange, 40 nmol/mg, yellow, 250 nmol/mg, and 500 nmol/mg Ca2+ condition. Data are presented as the mean ± standard deviation for a sample size of n ≥ 8.CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Andrade, L.O. (2019). Chapter Three—Annexins and Plasma Membrane Repai. Plasma Membrane Repair, Elsevier.

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Metadata

Authors
Walkon, L. L., Strubbe-Rivera, J. O., & Bazil, J. N.
Affiliations
  • Michigan State University (US)
  • Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
ORCID
Venue
Biomolecules
Publisher
MDPI AG
Published
2022-12-17
Volume
12
Issue
12
Pages
1891
ISSN
2218-273X (ISSN-L)
DOI
10.3390/biom12121891
PMC
PMC9775684
OpenAlex
W4313236994
Cited by
187
References
95
Citations by year
2026: 50 · 2025: 75 · 2024: 50 · 2023: 12
FWCI
3.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomolecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (F31HL152623)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
mitochondrial calcium overload, mitochondrial calcium retention capacity, ATP synthesis inhibition, oxidative phosphorylation, mitochondrial ultrastructure, cryo-electron microscopy, mitochondrial function
MeSH terms
Adenosine Triphosphate, Calcium, Energy Metabolism, Mitochondria, Cryoelectron Microscopy

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