Mitochondria Functionality and Sperm Quality
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REPRODUCTIONREVIEW Mitochondria functionality and sperm quality Alexandra Amaral1,2,3,Ba´rbara Lourenc¸o1,Mo´nica Marques1,4 and Joa˜o Ramalho-Santos1,4 1Biology of Reproduction and Stem Cell Group, CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal, 2Human Genetics Research Group, IDIBAPS, Faculty of Medicine, University of Barcelona, Casanova 143, 08036 Barcelona, Spain, 3Biochemistry and Molecular Genetics Service, Clinic Hospital, Villarroel 170, 08036 Barcelona, Spain and 4Department of Life Sciences, University of Coimbra, PO Box 3046, 3001-401 Coimbra, Portugal Correspondence should be addressed to J Ramalho-Santos at Department of Life Sciences, University of Coimbra; Email: [email protected] Abstract Although mitochondria are best known for being the eukaryotic cell powerhouses, these organelles participate in various cellular functions besides ATP production, such as calcium homoeostasis, generation of reactive oxygen species (ROS), the intrinsic apoptotic pathway and steroid hormone biosynthesis. The aim of this review was to discuss the putative roles of mitochondria in mammalian sperm function and how they may relate to sperm quality and fertilisation ability, particularly in humans. Although paternal mitochondria are degraded inside the zygote, sperm mitochondrial functionality seems to be critical for fertilisation. Indeed, changes in mitochondrial integrity/functionality, namely defects in mitochondrial ultrastructure or in the mitochondrial genome, transcriptome or proteome, as well as low mitochondrial membrane potential or altered oxygen consumption, have been correlated with loss of sperm function (particularly with decreased motility). Results from genetically engineered mouse models also confirmed this trend. On the other hand, increasing evidence suggests that mitochondria derived ATP is not crucial for sperm motility and that glycolysis may be the main ATP supplier for this particular aspect of sperm function. However, there are contradictory data in the literature regarding sperm bioenergetics. The relevance of sperm mitochondria may thus be associated with their role in other physiological features, particularly with the production of ROS, which in controlled levels are needed for proper sperm function. Sperm mitochondria may also serve as C intracellular Ca2 stores, although their role in signalling is still unclear. Reproduction (2013) 146 R163–R174 The mitochondrion: a multidimensional organelle membrane (OMM) and inner mitochondrial membrane (IMM), the intermembrane space and the mitochondrial Mitochondria are important and unique organelles, and matrix (Fig. 1). The similarities between the IMM and ongoing research keeps highlighting novel ways in the cellular membrane of prokaryotic organisms which they participate in cellular functions. One main (including the presence of the lipid cardiolipin), together characteristic that separates the mitochondrion from with the existence of mtDNA, stress the possibility that other organelles is the presence of its own circular mitochondria were once symbionts inside the cell, genome, mitochondrial DNA (mtDNA) and specific which progressively lost autonomy as most of their ribosomes, thus allowing for local protein synthesis genome migrated to the nucleus, resulting in a full (St John et al. 2010). Although mtDNA only codes for integration and control of mitochondria in eukaryotes 13 mitochondrial proteins (Fig. 1), their expression might (Alberts et al. 2008). be essential for mitochondrial function. To this extent, The IMM is usually convoluted, presenting several mtDNA defects have been associated with a range of invaginations (cristae) but, unlike what is often assumed, human disorders (including neurodegenerative diseases this general arrangement is very variable, and the and cancer), as well as with ageing (for recent reviews, number, structure and extension of IMM cristae see Greaves et al. (2012) and Schon et al. (2012)). The may have functional consequences (Bereiter-Hahn & development of animal models harbouring mtDNA Jendrach 2010). Furthermore, mitochondrial morpho- mutations corroborated this association and contributed logy itself is also plastic, with components of specific to the elucidation of mitochondrial disease mechanisms mitochondrial fission and fusion machineries promoting (Dunn et al. 2012). reversible changes from ovoid mitochondria to exten- In addition, mitochondria feature four defined inter- sive interconnected filamentous organelles (Campello & connected compartments: the outer mitochondrial Scorrano 2010). Finally, the functional importance of q 2013 Society for Reproduction and Fertility DOI: 10.1530/REP-13-0178 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/25/2021 06:20:33AM via free access R164 A Amaral and others Atpenins, Antimycin A, Azide, Oligomycin, A Amytal, Rotenone TIFA Myxothiazol Cyanide DCCD Complex I Complex II Complex III Complex IV Complex V + 4H × + + 2 2H 2H 3H+ VIIb Proton NADH dehydrogenase Fumarate reductase ATP synthase channel (Escherichia coli) (Thermus themophilus) (E. coli) a Cyt c VIb Intermembrane 8 ISP Cyt IV II space VIa VIII 7 a Membrane domain VIc 10 Inter (hydrophobic arm) FrdD FrdC UQ Cyt b III F0 unit mitochondrial e– 11 c membrane H1 UQH2 I Nqo6 VIIa Nqo4 6 Vb Mitochondrial Iron Quinone Va b ε 1.9.3.1 γ matrix Nqo5 Nqo + + protein pool Core 1 9 VIIc 2H 4H Core 2 β β 9 Nqo Flavo protein 1.3.99.1 1.10.2.2 15 3 F1 unit FMN Hydrophilic 1.3.5.1 + H O 1/2O2 2H 2 α domain β α Nqo1 Nqo2 (peripheral arm) 2H+ Cytochrome c oxidase Cytochrome bcl complex Succinate (bovine) δ 3.6.3.14 3.6.3.10 1.6.5.3 Fumarate (bovine) 1.6.99.3 1.6.99.5 3.6.3.6 NADH + 2.7.4.1 3.6.1.1 NAD H+ PPPi PPi Pi ADP + 3H ATP H2O B NADH dehydrogenase (Complex I) E ND1 ND2 ND3 ND4 ND4L ND5 ND6 E Ndufs1 Ndufs2 Ndufs3 Ndufs4 Ndufs5 Ndufs6 Ndufs7 Ndufs8 Ndufv1 Ndufv2 Ndufv3 E Ndufa1 Ndufa2 Ndufa3 Ndufa4 Ndufa5 Ndufa6 Ndufa7 Ndufa8 Ndufa9 Ndufa10 Ndufb1 Ndufb11 Ndufb12 Ndufb13 E Ndufb1 Ndufb2 Ndufb3 Ndufb4 Ndufb5 Ndufb6 Ndufb7 Ndufb8 Ndufb9 Ndufb10 Ndufb11 Ndufc1 Ndufc2 Succinate dehydrogenase/fumarate reductase (Complex II) E SDHC SDHD SDHA SDHB Cytochrome c reductase (Complex III) E/B/A ISP Cytb Cyt1 E COR1 QCR2 QCR6 QCR7 QCR8 QCR9 QCR10 Cytochrome c oxidase (Complex IV) E/B/A E COX10 COX3 COX1 COX2 COX4 COX5A COX5B COX6A COX6B COX6C COX7A COX7B COX7C COX8 COX17 COX11 COX15 F-type ATPase (Eukaryotes) beta alpha gamma OSCP delta epsilon ca b e f6 f g d fhj k g V-type ATPase (Eukaryotes) A BCDEF GH I AC39 54kD S1 lipid Figure 1 The mitochondrial electron transfer chain (ETC) and the production of ATP by oxidative phosphorylation. (A) The structure, composition and localisation of the ETC complexes is represented. Examples of inhibitors of each of the complexes are also indicated. (B) Proteins constituting each of the complexes. Adapted from the KEGG Pathway Database (http://www.genome.jp/kegg/pathway.html; Kanehisa et al. 2012). Details: pink rectangles, proteins described in human sperm proteomic studies (Amaral et al. 2013); green rectangles, proteins likely to be present but that have not been detected in human sperm proteomic projects; white rectangles, prokaryotic proteins; rectangles with blue frame, proteins encoded by the mitochondrial genome (all the others are nuclear encoded). mitochondrial connections to other organelles (such as transports electrons obtained from the oxidation of the endoplasmic reticulum) and the cytoskeleton is NADH and the FADH2 moiety of succinate dehydro- gaining attention, as it may help to integrate distinct genase, ultimately reducing the final acceptor oxygen to cellular functions (Anesti & Scorrano 2006, Rowland & water. In this process, a quimio-osmotic proton gradient Voeltz 2012). is generated across the IMM and is subsequently used Mitochondria participate in many crucial processes by the ATP synthase to phosphorylate ADP to ATP. The in eukaryotic cells, the better known of which is the proton gradient has two components, a minor chemical production of ATP via oxidative phosphorylation (pH) component and a major electric component, (OXPHOS), which is preceded by the generation of which is usually translated into the mitochondrial reduced electron carriers, both in the cytoplasm (via membrane potential (MMP). The electric nature of the glycolysis) and in the mitochondrial matrix (where the MMP (with a negatively charged mitochondrial matrix) Krebs cycle and the oxidation of most fatty acids take can also be harnessed to sequester calcium ions and place, Fig. 2). The IMM includes several complexes that thus participate in calcium homoeostasis (Nichols & make up the electron transfer chain (ETC, Fig. 1A), which Ferguson 2002). Reproduction (2013) 146 163–174 www.reproduction-online.org Downloaded from Bioscientifica.com at 09/25/2021 06:20:33AM via free access Mitochondria in human sperm R165 Figure 2 Overview of the pathways likely to be active in mammalian sperm mitochondria. Energy production by OXPHOS: the Krebs cycle and fatty acid b-oxidation contribute reducing equivalents to the electron transfer chain (ETC); ATP produced is exported from the matrix and ADP is C imported. The proton (H ) gradient may be dissipated by uncoupling proteins, under certain conditions. OXPHOS-derived ATP seems to be crucial for sperm function, although it does not seem to have a central role in sperm motility. Reactive oxygen species (ROS) production (which can be counteracted by antioxidant